2-amino-n-heteroaryl-nicotinamides as Nav1.8 inhibitors

ABSTRACT

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Na v 1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Na v 1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This U.S. Non-provisional application claims priority from and thebenefit of U.S. Provisional Application No. 62/754,742, filed Nov. 2,2018.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSC) mediate the selective influx ofsodium ions in excitable cells and play a central role in initiating andpropagating action potentials (Yu et al., Genome Biology 4:207 (2003)).Voltage-gated sodium channels are ubiquitous in the central andperipheral nervous system where they play a central role in theinitiation and propagation of action potentials, and also in skeletaland cardiac muscle where the action potential triggers cellularcontraction (Goldin et al., Ann N Y Acad Sci. 1999 Apr. 30; 868:38-50).Alterations in VGSC function or their expression can profoundly affectnormal cell excitability (Huang et al., J Neurosci. 2013 Aug. 28; 33(35):14087-97; Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81;Kist et al., PLoS One. 2016 Sep. 6; 11(9):e0161789; and Schreiber etal., World J Diabetes. 2015 Apr. 15; 6(3):432-44).

Voltage-gated sodium channels are multimeric complexes characterized byone α-subunit, which forms an ion-conducting aqueous pore, and at leastone β-subunit that modifies the kinetics and voltage-dependence of thechannel gating. Nine different α-subunits have been identified andcharacterized in mammalian voltage-gated sodium channels, includingNa_(v)1.8, also known as SNS, PN3 or Na_(v)1.8 (Goldin et al., Neuron.2000 November; 28 (2):365-8).

Expression of sodium channels can be tissue specific. Na_(v)1.8voltage-gated sodium ion channels are expressed primarily in sensoryneurons, which are responsible for conveying information from theperiphery (e.g. skin, muscle and joints) to the central nervous systemvia the spinal cord. Sodium channels are integral to this process assodium channel activity is required for initiation and propagation ofaction potentials triggered by noxious stimuli (thermal, mechanical andchemical) activating peripheral nociceptors (Catterall et al., Nat ChemBiol. 2017 Apr. 13; 13(5):455-463). An increase in VGSC protein level atthe cell surface or an alteration in activity of the VGSC channels canresult in disease states such as migraine, neurodegeneration followingischemia, epilepsies, and chronic neuropathic and inflammatory painstates. Gain of function mutations in Nav1.7, Nav1.8, and Nav1.9manifest in a variety of pain syndromes where patients experiencespontaneous pain without an external stimulus (Bennett et al., LancetNeurol. 2014 June; 13(6):587-99; Huang et al., J Neurosci. 2013 Aug. 28;33(35):14087-97; Kist et al., PLoS One. 2016 Sep. 6; 11(9):e0161789;Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81; and Schreiber etal., World J Diabetes. 2015 Apr. 15; 6(3):432-44).

Na_(v)1.8 voltage-gated sodium ion channels are believed to play a rolein various maladies, including neuropathic pain, chronic itch, andinflammatory pain perception (Belkouch et al., J Neuroinflammation. 2014Mar. 7; 11:45; Coward et al., Pain. 2000 March; 85(1-2):41-50; Yiangouet al., FEBS Lett. 2000 Feb. 11; 467(2-3):249-52; Black et al., AnnNeurol. 2008 December; 64(6):644-53; Bird et al., Br J Pharmacol. 2015May; 172(10):2654-70; Liu et al., Neuron. 2010 Nov. 4; 68(3):543-56; andZhao et al., J Clin Invest. 2013).

Large portions of the voltage gated sodium ion channels are conservedamong the various subtypes, therefore there is a potential for producingserious side effects when utilizing therapeutic agents that do notdemonstrate subtype selectivity. Therefore, therapeutic agents suitablefor use in addressing nociception, cough, or itch disorders, requirespecificity in their action, for example, discriminating between actionupon Na_(v)1.5 sodium ion channels, thought to be important inregulation of cardiac function, and action upon Na_(v)1.8 sodium ionchannels, thought to be central in inflammatory nociception, or itch anddisorders arising from dysfunctional and/or upregulated Na_(v)1.8 sodiumion channels.

Accordingly, it is believed that inhibitors of Na_(v)1.8 voltage-gatedsodium ion channel activity may useful to treat or prevent diseases,disorders and conditions involving Na_(v)1.8 receptors and/or stemmingspecifically from dysfunction of Na_(v)1.8 voltage-gated sodium ionchannels (Han et al., J Neurol Neurosurg Psychiatry 2014 May;85(5):499-505), including but not limited to, migraine,neurodegeneration following ischemia, epilepsy, inflammatory pain,spontaneous pain, acute pain, preoperative pain, perioperative pain,post-operative pain, neuropathic pain, chronic itch, and itch disorders.

There remains a need for potent Na_(v)1.8 sodium ion channel activityinhibitors with selective activity for Na_(v)1.8 sodium ion channels. Asa result, the compounds of the present invention are useful for thetreatment and prevention of diseases, disorders and conditions involvingNa_(v)1.8 receptors and Na_(v)1.8 voltage-gated sodium ion channels.

The role of Nav1.8 sodium ion channels is discussed in: Bennett et al.,Physical Medicine and Rehabilitation Clinics of North America, 2001,12(2):447-459; Meissner et al., Br J Sports Med. 2018 May;52(10):642-650; Legroux-Crespel et al., Neurology. 2016 Feb. 2;86(5):473-83; and Flaxman et al., Lancet, 380:2163-2196 (2012).

Compounds useful to treat Na_(v)1.8 sodium ion channel relatedconditions are disclosed in: ACS Med. Chem. Lett. 2015, 6, 650; BJP2015, 172, 2654; PNAS 2007, 104, 8520; J. Med. Chem. 2008, 51, 407; JPET2008, 324, 1204; and Neuropharmacology 2010, 59, 201.

Na_(v)1.8 compounds are also disclosed in: WO 2009/049180, WO2009/049181, WO 2009/049183, WO 2014/120808; WO 2014/120815; WO2014/120820; WO 2015/010065; and WO 2015/089361; WO 2017/209322; U.S.Pat. Nos. 8,519,137; 9,051,270; 9,108,903; 9,163,042; and 9,783,501.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of structural formulaI:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and embodiments thereof, are inhibitors ofNa_(v)1.8 sodium ion channel activity (or Na_(v)1.8 inhibitors) and maybe useful in the treatment and prevention of diseases, disorders andconditions mediated by Na_(v)1.8 sodium ion channel activity, such asnociception, osteoarthritis, peripheral neuropathy, inheritederythromelalgia, multiple sclerosis, asthma, itch, atopy, allergic orcontact dermatitis, renal failure, cholestasis, pruritus, acute itch,chronic itch, migraine, neurodegeneration following ischemia, epilepsy,pain, inflammatory pain, spontaneous pain, acute pain, acute pain due tofractures, musculoskeletal damage, pancreatitis and renal colic,peri-operative pain, post-operative pain, neuropathic pain, postherpeticneuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower backpain, phantom limb pain, sciatica, pain caused by 2° or 3° burn injury,optic neuritis, pain resulting from cancer and chemotherapy, chronicpelvic pain, pain syndromes, and complex regional pain syndromes. In oneembodiment of the present invention, the condition, disease or disorderis a pain disorder, an acute pain disorder or chronic pain disorder. Inanother embodiment of the present invention, the condition, disease ordisorder is an acute pain disorder.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment,management, prevention, alleviation, amelioration, suppression orcontrol of disorders, diseases, and conditions that may be responsive toinhibition of Na_(v)1.8 sodium ion channel activity in a subject in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

The present invention also relates to the use of compounds of thepresent invention for manufacture of a medicament useful in treatingdiseases, disorders and conditions that may be responsive to theinhibition of Na_(v)1.8 sodium ion channel activity.

The present invention is also concerned with treatment or prevention ofthese diseases, disorders and conditions by administering the compoundsof the present invention in combination with a therapeutically effectiveamount of another agent that may be useful to treat the disease,disorder and condition. The invention is further concerned withprocesses for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof, whereinA is heteroaryl or heteroaryl fused to a saturated or unsaturated 5- or6-membered ring containing 0-3 heteroatoms independently selected fromO, S and N(R^(h))_(q), wherein each heteroaryl, 5-membered ring and6-membered ring is unsubstituted or substituted with one to fivesubstituents selected from R^(a);

B is heteroaryl, wherein heteroaryl is unsubstituted or substituted withone to three substituents selected from R^(b);

R¹ is selected from the group consisting of:

(1) hydrogen,

(2) —SO₃H,

(3) —SO₂NH₂,

(4) —SO₂NR^(e)C₁₋₆alkyl,

(5) —SO₂NR^(e)C(O)C₁₋₆alkyl,

(6) —SO₂NR^(e)C₂₋₆alkenyl,

(7) —SO₂NR^(e)C₃₋₆cycloalkyl,

(8) —SO₂NR^(e)C(O)C₃₋₆cycloalkyl,

(9) —SO₂NR^(e)C₂₋₆cycloheteroalkyl,

(10) —SO₂NR^(e)C(O)C₂₋₆cycloheteroalkyl,

(11) —SO₂NR^(e)-aryl,

(12) —SO₂NR^(e)-heteroaryl,

(13) —SO₂C₁₋₆alkyl,

(14) —SO₂C₁₋₆alkenyl,

(15) —SO₂C₃₋₆cycloalkyl,

(16) —SO₂C₂₋₆cycloheteroalkyl,

(17) —SO₂aryl,

(18) —SO₂heteroaryl,

(19) —S(O)R^(j),

(20) —SR^(j),

(21) —C(O)NH₂,

(22) —C(O)NR^(e)R^(j),

(23) —CO²H,

(24) —CO²R^(j),

(25) —C(O)R^(j),

(26) —CN,

(27) CF₃,

(28) halogen,

(29) —OH,

(30) —OC₁₋₆alkyl,

(31) —OC₂₋₆alkenyl,

(32) —OC₃₋₆cycloalkyl,

(33) —OC₂₋₆cycloheteroalkyl,

(34) —O-aryl,

(35) —O-heteroaryl,

(36) —OC(O)R^(j),

(37) —OC(O)NR^(e)R^(j),

(38) —OC(O)N(R^(j))₂,

(39) —C₁₋₆alkyl,

(40) —C₂₋₆alkenyl,

(41) —C₁₋₆cycloalkyl,

(42) —C₂₋₆cycloheteroalkyl,

(43) aryl,

(44) heteroaryl,

(45) —(CH₂)_(n)NR^(e)C(O)R^(j),

(46) —(CH₂)_(n)NR^(e)C(O)OR^(j),

(47) —(CH₂)_(n)NR^(e)C(O)N(R^(e))₂,

(48) —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j),

(49) —(CH₂)_(n)NR^(e)C(O)N(R^(j))₂,

(50) —(CH₂)_(n)NR^(e)S(O)_(m)R^(j),

(51) —(CH₂)_(n)NR^(e)S(O)_(m)N(R^(e))₂,

(52) —(CH₂)_(n)NR^(e)S(O)_(m)NR^(e)R^(j),

(53) —(CH₂)_(n)NR^(e)S(O)_(m)N(R^(j))₂, and

(54) —(CH₂)_(n)NR^(e)R^(j),

wherein each CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to four substituentsselected from R^(d);

R² is selected from the group consisting of:

-   -   1) hydrogen, and    -   2) —C₁₋₆alkyl;        R³ is selected from the group consisting of:    -   1) a monocyclic, bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring,        and    -   2) a monocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl        ring, wherein the cycloheteroalkyl contains 1-4 heteroatoms        independently selected from N(R^(m))_(r), O, and S, wherein each        cycloalkyl ring and each cycloheteroalkyl ring may be fused to        an aryl or heteroaryl, and wherein each cycloalkyl,        cycloheteroalkyl, aryl and heteroaryl is unsubstituted or        substituted with one to eight substitutents selected from R^(c);        each R^(a) is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —OC₁₋₆alkyl,

(3) halogen,

(4) —OH,

(5) oxo,

(6) —CN,

(7) —C₃₋₆cycloalkyl, and

(8) —C₂₋₅cycloheteroalkyl,

wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to six substituents selected from halogen, OH, NH₂,NH(C₁₋₆alkyl) and N(C₁₋₆alkyl)₂;

each R^(b) is independently selected from the group consisting of:

(1) —CF₃,

(2) —CF₂CF₃;

(3) —CHF₂,

(4) —OCHF₂,

(5) —OCH₂CF₃,

(6) —OCF₃,

(7) CN,

(8) halogen,

(9) —Si(C₁₋₆alkyl)₃,

(10) —C₁₋₆alkyl-O—R^(k),

(11) —C₁₋₆alkyl,

(12) —C₂₋₆alkenyl,

(13) —C₂₋₆alkynyl,

(14) —C₃₋₆cycloalkyl,

(15) —C₂₋₆cycloheteroalkyl,

(16) aryl,

(17) heteroaryl,

(18) —C₁₋₆alkyl-C₃₋₆cycloalkyl,

(19) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,

(20) —C₁₋₆alkyl-aryl,

(21) —C₁₋₆alkyl-heteroaryl,

(22) —C₂₋₆alkenyl-C₃₋₆cycloalkyl,

(23) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,

(24) —C₂₋₆alkenyl-aryl,

(25) —C₂₋₆alkenyl-heteroaryl,

(26) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,

(27) —C₂₋₆alkynyl cycloheteroalkyl,

(28) —C₂₋₆alkynyl-aryl,

(29) —C₂₋₆alkynyl-heteroaryl,

(30) NO₂,

(31) —OH,

(32) —(CH₂)_(p)—OC₁₋₆alkyl,

(33) —(CH₂)_(p)—OC₂₋₆alkenyl,

(34) —(CH₂)_(p)—OC₂₋₆alkynyl,

(35) —(CH₂)_(p)—OC₃₋₆cycloalkyl,

(36) —(CH₂)_(p)—OC₂₋₆heterocycloalkyl,

(37) —(CH₂)_(p)—O-aryl,

(38) —(CH₂)_(p)—O-heteroaryl,

(39) —OC₁₋₆alkyl-C₃₋₆cycloalkyl,

(40) —OC₁₋₆alkyl-C₂₋₆heterocycloalkyl,

(41) —OC₁₋₆alkyl-aryl,

(42) —OC₁₋₆alkyl-heteroaryl,

(55) —S(O)_(m)R^(k),

(43) —C₁₋₆alkyl-S(O)_(m)R^(k),

(44) —C(O)R^(k),

(45) —N(R^(i))₂, and

(46) —NR^(i)R^(k),

wherein each R^(b) is unsubstituted or substituted with one to fivesubstituents selected from R^(f);

each R^(c) is independently selected from the group consisting of:

(1) —CF₃,

(2) —CH₂CF₃,

(3) —CHF₂,

(4) —OCHF₂,

(5) —OCF₃,

(6) CN,

(7) oxo,

(8) —OH,

(9) halogen,

(10) —C₁₋₆alkyl,

(11) —C₂₋₆alkenyl,

(12) —C₂₋₆alkynyl,

(13) —C₃₋₆cycloalkyl,

(14) —C₂₋₆cycloheteroalkyl,

(15) —C₁₋₆alkyl-C₃₋₆cycloalkyl,

(16) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,

(17) —C₁₋₆alkyl-aryl,

(18) —C₁₋₆alkyl-heteroaryl,

(19) —C₁₋₆alkenyl-C₃₋₆cycloalkyl,

(20) —C₁₋₆alkenyl-aryl,

(21) —C₁₋₆alkenyl heteroaryl,

(22) —C₁₋₆alkenyl-C₂₋₆cycloheteroalkyl,

(23) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,

(24) —C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl,

(25) —C₂₋₆alkynyl-aryl,

(26) —C₂₋₆alkynyl heteroaryl,

(27) —OC₁₋₆alkyl,

(28) —OC₂₋₆ alkenyl,

(29) —OC₂₋₆ alkynyl,

(30) —OC₃₋₆ cycloalkyl,

(31) —OC₂₋₆ heterocycloalkyl,

(32) —O-aryl,

(33) —O-heteroaryl,

(34) —OC₁₋₆alkyl-cycloalkyl,

(35) —OC₁₋₆alkyl-cycloheteroalkyl,

(36) —OC₁₋₆alkyl-aryl,

(37) —OC₁₋₆ alkyl-heteroaryl,

(38) —S(O)_(m)R^(L),

(39) —S(O)R^(L),

(40) —S—R^(L),

(41) —C₁₋₆alkyl-S(O)_(m)R^(L),

(42) —C(O)R^(L),

(43) —C(O)C₁₋₆alkyl-R^(L),

(44) —OC(O)R^(L),

(45) —CO₂R^(L),

(46) aryl, and

(47) heteroaryl,

wherein each R^(c) is unsubstituted or substituted with one to fivesubstituents selected from R^(g);

R^(d) is independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) OH,

(4) oxo,

(5) —C₁₋₆alkyl,

(6) —OC₁₋₆alkyl,

(7) NH₂,

(8) NH(C₁₋₆alkyl), and

(9) N(C₁₋₆alkyl)₂;

each R^(e) is independently selected from the group consisting of:

(1) hydrogen,

(2) —C₁₋₆alkyl, and

(3) C₂₋₆alkenyl;

each R^(f) is selected from the group consisting of:

(1) halogen, F

(2) —C₁₋₆alkyl,

(3) —OH,

(4) —OC₁₋₆alkyl,

(5) —OC₃₋₆cycloalkyl,

(6) —OC₂₋₆cycloheteroalkyl,

(7) CN,

(8) —NH₂,

(9) —NH(C₁₋₆alkyl),

(10) —NH(C₃₋₆cycloalkyl),

(11) —NH(C₂₋₆cycloheteroalkyl),

(12) —N(C₁₋₆alkyl)₂,

(13) —N(C₃₋₆cycloalkyl)₂, and

(14) —N(C₂₋₆cycloheteroalkyl)₂,

wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, halogen, cyano, and —S(O)₂CH₃; each R^(g) is selected from thegroup consisting of:

(1) halogen,

(2) C₁₋₆alkyl,

(3) —OH,

(4) —OC₁₋₆alkyl,

(5) —S(O)_(m)—C₁₋₆alkyl,

(6) —CN,

(7) —CF₃,

(8) —OCHF₂, and

(9) —OCF₃,

wherein each alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, cyano, and—S(O)₂CH₃;

each R^(h) is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C₁₋₆alkyl;

each R^(i) is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C₁₋₆alkyl;

each R^(j) is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —C₂₋₆alkenyl,

(3) —C₃₋₆cycloalkyl,

(4) —C₂₋₆cycloheteroalkyl,

(5) aryl, and

(6) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃;each R^(k) is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —C₂₋₆alkenyl,

(3) —C₃₋₆cycloalkyl,

(4) —C₃₋₆cycloalkyl,

(5) —C₂₋₆cycloheteroalkyl,

(6) aryl, and

(7) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃;each R^(L) is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —C₂₋₆alkenyl,

(3) —C₃₋₆cycloalkyl,

(4) —C₂₋₆cycloheteroalkyl,

(5) aryl, and

(6) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃;each R^(m) is independently selected from the group consisting of:

(1) hydrogen, and

(2) —C₁₋₆alkyl;

each n is independently 0, 1, 2, 3 or 4;

each m is independently 0, 1 or 2;

each p is independently 0, 1, 2, 3 or 4;

each q is independently 0 or 1; and

each r is independently 0 or 1.

The invention has numerous embodiments, which are summarized below. Theinvention includes the compounds as shown, and also includes individualdiastereoisomers, enantiomers, and epimers of the compounds, andmixtures of diastereoisomers and/or enantiomers thereof includingracemic mixtures.

In one embodiment of the present invention, A is heteroaryl orheteroaryl fused to a saturated or unsaturated 5- or 6-membered ringcontaining 0-3 heteroatoms independently selected from O, S andN(R^(h))_(q), wherein each heteroaryl, 5-membered ring and 6-memberedring is unsubstituted or substituted with one to five substituentsselected from R^(a). In a class of this embodiment, A is unsubstitutedor substituted with one to four substituents selected from R^(a). Inanother class of this embodiment, A is unsubstituted or substituted withone to three substituents selected from R^(a). In another class of thisembodiment, A is unsubstituted or substituted with one to twosubstituents selected from R^(a). In another class of this embodiment, Ais unsubstituted or substituted with one substituent selected fromR^(a). In another class of this embodiment, A is substituted with onesubstituent selected from R^(a). In another class of this embodiment Ais not substituted with a substituent selected from R^(a). In anotherclass of this embodiment A is unsubstituted.

In another embodiment of the present invention, A is heteroaryl orheteroaryl fused to a saturated or unsaturated 5- or 6-membered ringcontaining 0-3 heteroatoms independently selected from O, S andN(R^(h))_(q), wherein each heteroaryl, 5-membered ring and 6-memberedring is unsubstituted or substituted with one to four substituentsselected from R^(a). In a class of this embodiment, A is unsubstitutedor substituted with one to three substituents selected from R^(a).

In another class of this embodiment, A is unsubstituted or substitutedwith one to two substituents selected from R^(a). In another class ofthis embodiment, A is unsubstituted or substituted with one substituentselected from R^(a). In another class of this embodiment, A issubstituted with one substituent selected from R^(a). In another classof this embodiment A is not substituted with a substituent selected fromR^(a). In another class of this embodiment A is unsubstituted.

In another embodiment, A is heteroaryl, wherein heteroaryl isunsubstituted or substituted with one to four substituents selected fromR^(a). In a class of this embodiment, A is unsubstituted or substitutedwith one to three substituents selected from R^(a). In another class ofthis embodiment, A is unsubstituted or substituted with one to twosubstituents selected from R^(a).

In another class of this embodiment, A is unsubstituted or substitutedwith one substituent selected from R^(a). In another class of thisembodiment, A is substituted with one substituent selected from R^(a).In another class of this embodiment A is not substituted with asubstituent selected from R^(a). In another class of this embodiment Ais unsubstituted.

In another embodiment, A is selected from the group consisting of:pyridine, pyrimidine, pyrazine, pyridazine, indazole,imidazo[1,2-a]pyridine, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, benzimidazole,imidazole, pyrazole, thiophene, furan, 1,2,4-oxadiazole,1,3,4-oxadiazole, oxazole, isoxazole, isothiazole, thiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 4H-pyrido[2,3-e][1,2,4]thiadiazine1,1-dioxide, 2H-pyrido[2,3-e][1,2]thiazine 1,1-dioxide,2,3-dihydroisothiazolo[4,5-b]pyridine 1,1-dioxide, and3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazine 1,1-dioxide, wherein A isunsubstituted or substituted with one to four substituents selected fromR^(a). In a class of this embodiment, A is unsubstituted or substitutedwith one to three substituents selected from R^(a). In another class ofthis embodiment, A is unsubstituted or substituted with one to twosubstituents selected from R^(a). In another class of this embodiment, Ais unsubstituted or substituted with one substituent selected fromR^(a). In another class of this embodiment, A is substituted with onesubstituent selected from R^(a). In another class of this embodiment Ais not substituted with a substituent selected from R^(a). In anotherclass of this embodiment A is unsubstituted.

In another embodiment, A is selected from the group consisting of:pyridine, pyrimidine, pyrazine, pyridazine, indazole,imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine,benzimidazole, imidazole, pyrazole, thiophene, furan, 1,2,4-oxadiazole,1,3,4-oxadiazole, oxazole, isoxazole, isothiazole, thiazole,1,2,4-thiadiazole, and 1,3,4-thiadiazole, wherein A is unsubstituted orsubstituted with one to four substituents selected from R^(a). In aclass of this embodiment, A is unsubstituted or substituted with one tothree substituents selected from R^(a). In another class of thisembodiment, A is unsubstituted or substituted with one to twosubstituents selected from R^(a). In another class of this embodiment, Ais unsubstituted or substituted with one substituent selected fromR^(a). In another class of this embodiment, A is substituted with onesubstituent selected from R^(a). In another class of this embodiment Ais not substituted with a substituent selected from R^(a). In anotherclass of this embodiment A is unsubstituted.

In another embodiment, A is selected from the group consisting of:pyridine, pyrimidine, pyrazine, pyridazine, indazole,imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine,benzimidazole, imidazole, pyrazole, thiophene, 1,2,4-oxadiazole,1,3,4-oxadiazole, oxazole, isothiazole, thiazole, 1,2,4-thiadiazole, and1,3,4-thiadiazole, wherein A is unsubstituted or substituted with one tofour substituents selected from R^(a). In a class of this embodiment, Ais unsubstituted or substituted with one to three substituents selectedfrom R^(a). In another class of this embodiment, A is unsubstituted orsubstituted with one to two substituents selected from R^(a). In anotherclass of this embodiment, A is unsubstituted or substituted with onesubstituent selected from R^(a). In another class of this embodiment, Ais substituted with one substituent selected from R^(a). In anotherclass of this embodiment A is not substituted with a substituentselected from R^(a). In another class of this embodiment A isunsubstituted.

In another embodiment, A is selected from the group consisting of:pyridine, pyrimidine, pyrazine, indazole, imidazo[1,2-a]pyridine,pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, pyrazole, thiophene, and1,2,4-oxadiazole, wherein A is unsubstituted or substituted with one tofour substituents selected from R^(a). In a class of this embodiment, Ais unsubstituted or substituted with one to three substituents selectedfrom R^(a). In another class of this embodiment, A is unsubstituted orsubstituted with one to two substituents selected from R^(a). In anotherclass of this embodiment, A is unsubstituted or substituted with onesubstituent selected from R^(a). In another class of this embodiment, Ais substituted with one substituent selected from R^(a). In anotherclass of this embodiment A is not substituted with a substituentselected from R^(a). In another class of this embodiment A isunsubstituted.

In another embodiment, A is selected from the group consisting of:pyridine, pyrimidine, pyrazine, pyridazine, indazole,imidazo[1,2-a]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine,pyrazole, thiophene, and 1,2,4-oxadiazole, wherein A is unsubstituted orsubstituted with one to four substituents selected from R^(a). In aclass of this embodiment, A is unsubstituted or substituted with one tothree substituents selected from R^(a). In another class of thisembodiment, A is unsubstituted or substituted with one to twosubstituents selected from R^(a). In another class of this embodiment, Ais unsubstituted or substituted with one substituent selected fromR^(a). In another class of this embodiment, A is substituted with onesubstituent selected from R^(a). In another class of this embodiment Ais not substituted with a substituent selected from R^(a). In anotherclass of this embodiment A is unsubstituted.

In another embodiment, A is selected from the group consisting of:pyridine, pyrimidine, and pyrazine, wherein A is unsubstituted orsubstituted with one to four substituents selected from R^(a). In aclass of this embodiment, A is unsubstituted or substituted with one tothree substituents selected from R^(a). In another class of thisembodiment, A is unsubstituted or substituted with one to twosubstituents selected from R^(a). In another class of this embodiment, Ais unsubstituted or substituted with one substituent selected fromR^(a). In another class of this embodiment, A is substituted with onesubstituent selected from R^(a). In another class of this embodiment Ais not substituted with a substituent selected from R^(a). In anotherclass of this embodiment A is unsubstituted.

In another embodiment, A is pyridine, wherein pyridine is unsubstitutedor substituted with one to three substituents selected from R^(a). In aclass of this embodiment, A is unsubstituted or substituted with one totwo substituents selected from R^(a). In another class of thisembodiment, A is unsubstituted or substituted with one substituentselected from R^(a). In another class of this embodiment, A issubstituted with one substituent selected from R^(a). In another classof this embodiment A is not substituted with a substituent selected fromR^(a). In another class of this embodiment A is unsubstituted.

In another embodiment, A is

In another embodiment, A is

In another embodiment, A is

In another embodiment, A is

In another embodiment, A is:

In another embodiment, A is:

In another embodiment, B is heteroaryl, wherein heteroaryl isunsubstituted or substituted with one to three substituents selectedfrom R^(b). In a class of this embodiment, B is unsubstituted orsubstituted with one to two substituents selected from R^(b). In anotherclass of this embodiment, B is unsubstituted or substituted with onesubstituent selected from R^(b). In another class of this embodiment, Bis not substituted with a substituent selected from R^(b). In anotherclass of this embodiment B is unsubstituted.

In another embodiment of the present invention, B is selected from thegroup consisting of: pyrazine, pyridine, pyrimidine, and pyridazine,wherein each B is unsubstituted or substituted with one to threesubstituents selected from R^(b). In a class of this embodiment, B isunsubstituted or substituted with one or two substituents selected fromR^(b). In another class of this embodiment, B is unsubstituted orsubstituted with one substituent selected from R^(b). In another classof this embodiment, B is substituted with one substituent selected fromR^(b). In another class of this embodiment, B is not substituted with asubstituent selected from R^(b). In another class of this embodiment Bis unsubstituted.

In another embodiment, B is pyrazine, wherein pyrazine is unsubstitutedor substituted with one to three substituents selected from R^(b). Inanother embodiment, B is pyrazine, wherein pyrazine is unsubstituted orsubstituted with one or two substituents selected from R^(b). In anotherembodiment, B is pyrazine, wherein pyrazine is unsubstituted orsubstituted with one substituent selected from R^(b). In anotherembodiment, B is pyrazine, wherein pyrazine is substituted with onesubstituent selected from R^(b). In another class of this embodiment,pyrazine is not substituted with a substituent selected from R^(b). Inanother class of this embodiment, pyrazine is unsubstituted.

In another embodiment, B is selected from the group consisting of:pyridine, pyrimidine, and pyridazine, wherein each B is unsubstituted orsubstituted with one to three substituents selected from R^(b). In aclass of this embodiment, B is unsubstituted or substituted with one totwo substituents selected from R^(b). In another class of thisembodiment, B is unsubstituted or substituted with one substituentselected from R^(b). In another class of this embodiment, B issubstituted with one substituent selected from R^(b). In another classof this embodiment, B is not substituted with a substituent selectedfrom R^(b). In another class of this embodiment B is unsubstituted.

In another embodiment, B is pyridazine, wherein pyridazine isunsubstituted or substituted with one to three substituents selectedfrom R^(b). In another embodiment, B is pyridazine, wherein pyridazineis unsubstituted or substituted with one or two substituents selectedfrom R^(b). In another embodiment, B is pyridazine, wherein pyridazineis unsubstituted or substituted with one substituent selected fromR^(b). In another embodiment, B is pyridazine, wherein pyridazine issubstituted with one substituent selected from R^(b). In another classof this embodiment, pyridazine is not substituted with a substituentselected from R^(b). In another class of this embodiment, pyridazine isunsubstituted.

In another embodiment, B is pyrimidine, wherein pyrimidine isunsubstituted or substituted with one to three substituents selectedfrom R^(b). In another embodiment, B is pyrimidine, wherein pyrimidineis unsubstituted or substituted with one or two substituents selectedfrom R^(b). In another embodiment, B is pyrimidine, wherein pyrimidineis unsubstituted or substituted with one substituent selected fromR^(b). In another embodiment, B is pyrimidine, wherein pyrimidine issubstituted with one substituent selected from R^(b). In another classof this embodiment, pyrimidine is not substituted with a substituentselected from R^(b). In another class of this embodiment, pyrimidine isunsubstituted.

In another embodiment, B is pyridine, wherein pyridine is unsubstitutedor substituted with one to three substituents selected from R^(b). Inanother embodiment, B is pyridine, wherein pyridine is unsubstituted orsubstituted with one or two substituents selected from R^(b). In anotherembodiment, B is pyridine, wherein pyridine is unsubstituted orsubstituted with one substituent selected from R^(b). In anotherembodiment, B is pyridine, wherein pyridine is substituted with onesubstituent selected from R^(b). In another class of this embodiment,pyridine is not substituted with a substituent selected from R^(b). Inanother class of this embodiment, pyridine is unsubstituted.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, —SO₃H, —SO₂NH₂, —SO₂NR^(e)C₁₋₆alkyl,—SO₂NR^(e)C(O)C₁₋₆alkyl, —SO₂NR^(e)C₂₋₆alkenyl,—SO₂NR^(e)C₃₋₆cycloalkyl, —SO₂NR^(e)C(O)C₃₋₆cycloalkyl,—SO₂NR^(e)C₂₋₆cycloheteroalkyl, —SO₂NR^(e)C(O)C₂₋₆cycloheteroalkyl,—SO₂NR^(e)-aryl, —SO₂NR^(e)-heteroaryl, —SO₂C₁₋₆alkyl, —SO₂C₁₋₆alkenyl,—SO₂C₃₋₆cycloalkyl, —SO₂C₂₋₆cycloheteroalkyl, —SO₂aryl, —SO₂heteroaryl,—S(O)R^(j), —SR^(j), —C(O)NH₂, —C(O)NR^(e)R^(j), —CO₂H, —CO₂R^(j),—C(O)R^(j), —CN, CF₃, halogen, —OH, —OC₁₋₆alkyl, —OC₂₋₆alkenyl,—OC₃₋₆cycloalkyl, —OC₂₋₆cycloheteroalkyl, —O-aryl, —O-heteroaryl,—OC(O)R^(j), —OC(O)NR^(e)R^(j), —OC(O)N(R^(j))₂, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₁₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl,—(CH₂)_(n)NR^(e)C(O)R^(j), —(CH₂)_(n)NR^(e)C(O)OR^(j),—(CH₂)_(n)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(n)NR^(e)C(O)N(R^(j))₂, —(CH₂)_(n)NR^(e)S(O)_(m)R,—(CH₂)_(n)NR^(e)S(O)_(m)N(R^(e))₂, —(CH₂)_(n)NR^(e)S(O)_(m)NR^(e)R^(j),—(CH₂)_(n)NR^(e)S(O)_(m)N(R^(j))₂, and —(CH₂)_(n)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to four substituentsselected from R^(d);

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, —SO₃H, —SO₂NH₂, —SO₂NR^(e)C₁₋₆alkyl,—SO₂NR^(e)C₂₋₆alkenyl, —SO₂N(C₂₋₆alkenyl)₂, —SO₂NR^(e)C₃₋₆cycloalkyl,—SO₂NR^(e)C₂₋₆cycloheteroalkyl, —SO₂NR^(e)-aryl, —SO₂NR^(e)-heteroaryl,—SO₂C₁₋₆alkyl, —SO₂C₁₋₆alkenyl, —SO₂C₃₋₆cycloalkyl,—SO₂C₂₋₆cycloheteroalkyl, —SO₂aryl, —SO₂heteroaryl, —S(O)R^(j), —SR^(j),—C(O)NH₂, —C(O)NR^(e)R^(j), —CO₂H, —CO₂R^(j), —C(O)R, —CN, —CF₃,halogen, —OH, —OC₁₋₆alkyl, —OC₂₋₆alkenyl, —OC₃₋₆cycloalkyl,—OC₂₋₆cycloheteroalkyl, —O-aryl, —O-heteroaryl, —OC(O)R^(j),—OC(O)NR^(e)R^(j), —OC(O)N(R^(j))₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₁₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl,—(CH₂)_(n)NR^(e)C(O)R^(j), —(CH₂)_(n)NR^(e)C(O)OR^(j),—(CH₂)_(n)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(n)NR^(e)C(O)N(R^(j))₂, —(CH₂)_(n)NR^(e)S(O)_(m)R^(j),—(CH₂)_(n)NR^(e)S(O)_(m)N(R^(e))₂, —(CH₂)_(n)NR^(e)S(O)_(m)NR^(e)R^(j),—(CH₂)_(n)NR^(e)S(O)_(m)N(R^(j))₂, and —(CH₂)_(n)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to four substituentsselected from R^(d). In a class of this embodiment, each alkyl, alkenyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with one to three substituents selected from R^(d). Inanother class of this embodiment, each alkyl, alkenyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to two substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₃H, —SO₂NH₂, —SO₂NR^(e)C₁₋₆alkyl,—SO₂NR^(e)C₂₋₆alkenyl, —SO₂N(C₂₋₆alkenyl)₂, —SO₂NR^(e)C₃₋₆cycloalkyl,—SO₂NR^(e)C₂₋₆cycloheteroalkyl, —SO₂NR^(e)-aryl, —SO₂NR^(e)-heteroaryl,—SO₂C₁₋₆alkyl, —SO₂C₁₋₆alkenyl, —SO₂C₃₋₆cycloalkyl,—SO₂C₂₋₆cycloheteroalkyl, —SO₂aryl, —SO₂heteroaryl, —S(O)R^(j), —SR^(j),—C(O)NH₂, —C(O)NR^(e)R^(j), —CO₂H, —CO₂R^(j), —C(O)R^(j), —CN, —CF₃,halogen, —OH, —OC₁₋₆alkyl, —OC₂₋₆alkenyl, —OC₃₋₆cycloalkyl,—OC₂₋₆cycloheteroalkyl, —O-aryl, —O-heteroaryl, —OC(O)R^(j),—OC(O)NR^(e)R^(j), —OC(O)N(R^(j))₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₁₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl,—(CH₂)_(n)NR^(e)C(O)R^(j), —(CH₂)_(n)NR^(e)C(O)OR^(j),—(CH₂)_(n)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(n)NR^(e)C(O)N(R^(j))₂, —(CH₂)_(n)NR^(e)S(O)_(m)R^(j),—(CH₂)_(n)NR^(e)S(O)_(m)N(R^(e))₂, —(CH₂)_(n)NR^(e)S(O)_(m)NR^(e)R^(j),—(CH₂)_(n)NR^(e)S(O)_(m)N(R^(j))₂, and —(CH₂)_(n)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to four substituentsselected from R^(d). In a class of this embodiment, each alkyl, alkenyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with one to three substituents selected from R^(d). Inanother class of this embodiment, each alkyl, alkenyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to two substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂,—SO₂NH—C₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl,—SO₂C₃₋₆cycloheteroalkyl, —C(O)NH₂, —CO₂H, —CO₂C₁₋₆alkyl, —CN, halogen,—OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆cycloalkyl, CF₃,—SO₂NR^(e)C(O)C₁₋₆alkyl, —SO₂NR^(e)C(O)C₃₋₆cycloalkyl, and—SO₂NR^(e)C(O)C₂₋₆cycloheteroalkyl,

wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl isunsubstituted or substituted with one to four substituents selected fromR^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂,—SO₂NH—C₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl,—SO₂C₃₋₆cycloheteroalkyl, —C(O)NH₂, —CO₂H, —CO₂C₁₋₆alkyl, —CN, halogen,—OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆cycloalkyl, and CF₃,wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl isunsubstituted or substituted with one to four substituents selected fromR^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl, —SO₂NH—C₁₋₆alkyl,—SO₂N(C₁₋₆alkyl)₂, —SO₂C₃₋₆cycloalkyl, —SO₂C₃₋₆cycloheteroalkyl,—C(O)NH₂, —CO₂H, —CO₂C₁₋₆alkyl, —CN, halogen, —OH, —OC₁₋₆alkyl,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆cycloalkyl, and CF₃, wherein each alkyl,alkenyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to four substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂, —SO₂NH—C₁₋₆alkyl,—SO₂N(C₁₋₆alkyl)₂, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl,—SO₂C₃₋₆cycloheteroalkyl, —C(O)NH₂, —CO₂H, —CO₂C₁₋₆alkyl, —CN, halogen,—OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₁₋₆cycloalkyl, and CF₃,wherein each alkyl, alkenyl, cycloalkyl and cycloheteroalkyl isunsubstituted or substituted with one to four substituents selected fromR^(d).

In another embodiment, R¹ is hydrogen.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂,—SO₂NH—C₁₋₆alkyl, —SO₂N(C₁₋₆alkyl)₂, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl,—SO₂C₃₋₆cycloheteroalkyl, —C(O)NH₂, —CO₂H, —CO₂C₁₋₆alkyl, —CN, halogen,—OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-NH₂,—C₂₋₆alkenyl, —C₁₋₆cycloalkyl, and CF₃, wherein each alkyl, alkenyl,cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with oneto four substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl,—SO₂NH—C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl, —C(O)NH₂, —CO₂H, —CN, halogen,—OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₁₋₆cycloalkyl, and CF₃, wherein eachalkyl and cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: hydrogen, —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂,—SO₂NH—C₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl, —C(O)NH₂, —CO₂H,—CN, halogen, —OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH₂, —C₁₋₆cycloalkyl-OH, —C₁₋₆cycloalkyl-NH₂, and CF₃,wherein each alkyl and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂,—SO₂NH—C₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl, —C(O)NH₂, —CO₂H,—CN, halogen, —OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-NH₂, —C₁₋₆cycloalkyl-OH, —C₁₋₆cycloalkyl-NH₂, and CF₃,wherein each alkyl and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₃H, —SO₂NH₂, —SO₂C₁₋₆alkyl-NH₂,—SO₂NH—C₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SO₂C₃₋₆cycloalkyl, —C(O)NH₂, —CO₂H,—CN, halogen, —OH, —OC₁₋₆alkyl, —C₁₋₆alkyl, and CF₃, wherein each alkyl,and cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(d). In a class of this embodiment, R¹ isselected from the group consisting of: —SO₃H, —SO₂NH₂, —SO₂(CH₂)₂—NH₂,—SO₂NH—C(CH₃)₃, —SO₂CH₃, —SO₂CH₂CH₃, —SO₂- cyclopropyl, —C(O)NH₂, —CO₂H,—CN, F, Br, Cl, —OH, —OCH₃, —CH₃, —CH₂OH and —CF₃, wherein each alkyland cyclopropyl is unsubstituted or substituted with one to threesubstituents selected from R^(d).

In another class of this embodiment, R¹ is selected from the groupconsisting of: —SO₃H, —SO₂NH₂, —SO₂(CH₂)₂—NH₂, —SO₂NH—C(CH₃)₃, —SO₂CH₃,—SO₂CH₂CH₃, —SO₂- cyclopropyl, —C(O)NH₂, —CO₂H, —CN, F, Br, —OH, —OCH₃,—CH₃, —CH₂OH, and —CF₃, wherein each alkyl and cyclopropyl isunsubstituted or substituted with one to three substituents selectedfrom R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₂NR^(e)C(O)C₁₋₆alkyl,—SO₂NR^(e)C(O)C₃₋₆cycloalkyl, and —SO₂NR^(e)C(O)C₂₋₆cycloheteroalkyl,wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to four substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₂NH₂, —SO₂C₁₋₆alkyl, —SO₂NH—C₁₋₆alkyl,—SO₂C₃₋₆cycloalkyl, —C(O)NH₂, —CO₂H, —CN, halogen, —OH, —OC₁₋₆alkyl,—C₁₋₆alkyl, CF₃, —SO₂NR^(e)C(O)C₁₋₆alkyl, —SO₂NR^(e)C(O)C₃₋₆cycloalkyl,and —SO₂NR^(e)C(O)C₂₋₆cycloheteroalkyl, wherein each alkyl, andcycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₂NH₂, —SO₂C₁₋₆alkyl, —SO₂NH—C₁₋₆alkyl,—SO₂C₃₋₆cycloalkyl, —C(O)NH₂, —CO₂H, —CN, halogen, —OH, —OC₁₋₆alkyl,—C₁₋₆alkyl, and CF₃, wherein each alkyl, and cycloalkyl is unsubstitutedor substituted with one to three substituents selected from R^(d).

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: —SO₂NH₂, —C(O)NH₂, and —OH. In another embodimentof the present invention, R¹ is selected from the group consisting of:—SO₂NH₂ and —C(O)NH₂. In another embodiment of the present invention, R¹is —SO₂NH₂. In another embodiment of the present invention, R¹ is—C(O)NH₂. In another embodiment of the present invention, R¹ is —OH.

In another embodiment of the present invention, R² is selected from thegroup consisting of: hydrogen, and —C₁₋₆alkyl. In another embodiment, R²is —C₁₋₆alkyl. In another embodiment, R² is hydrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of: 1) a monocyclic, bicyclic or spirocyclicC₃₋₁₂cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4heteroatoms independently selected from N(R^(m))_(r), O, and S, whereineach cycloalkyl ring and each cycloheteroalkyl ring may be fused to anaryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryland heteroaryl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c). In a class of this embodiment, R³ isselected from the group consisting of: 1) a monocyclic, bicyclic orspirocyclic C₃₋₈cycloalkyl ring, and 2) a monocyclic, bicyclic orspirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkylcontains 1-4 heteroatoms independently selected from N(R^(m))_(r), O,and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring maybe fused to an aryl or heteroaryl, and wherein each cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to eight substitutents selected from R^(c). In another class ofthis embodiment, R³ is selected from the group consisting of: 1) amonocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and 2) amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains 1-4 heteroatoms independently selectedfrom NH, O, and S, wherein each cycloalkyl ring and eachcycloheteroalkyl ring may be fused to an aryl or heteroaryl, and whereineach cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstitutedor substituted with one to eight substitutents selected from R^(c). Inanother class of this embodiment, each cycloalkyl and cycloheteroalkylmay be fused to phenyl or thiene. In another class of this embodiment,each cycloalkyl and cycloheteroalkyl may be fused to phenyl. In anotherclass of this embodiment, each cycloalkyl and cycloheteroalkyl ring maybe fused to thiene. In another class of this embodiment and subclass ofthese classes, the cycloheteroalkyl contains nitrogen and is attached tothe B ring via a bond to the nitrogen. In another class of thisembodiment, R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to four substituentsselected from R^(c).

In another embodiment, R³ is selected from the group consisting of: 1) amonocyclic, bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring, and 2) amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains 1-4 heteroatoms independently selectedfrom N(R^(m))_(r), O, and S, wherein each cycloalkyl ring and eachcycloheteroalkyl ring may be fused to an aryl or heteroaryl, and whereineach cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstitutedor substituted with one to six substitutents selected from R^(c). In aclass of this embodiment, R³ is selected from the group consistingof: 1) a monocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and 2)a monocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring,wherein the cycloheteroalkyl contains 1-4 heteroatoms independentlyselected from N(R^(m))_(r), O, and S, wherein each cycloalkyl ring andeach cycloheteroalkyl ring may be fused to an aryl or heteroaryl, andwherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to six substitutents selected fromR^(c). In another class of this embodiment, R³ is selected from thegroup consisting of: 1) a monocyclic, bicyclic or spirocyclicC₃₋₈cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4heteroatoms independently selected from NH, O, and S, wherein eachcycloalkyl ring and each cycloheteroalkyl ring may be fused to an arylor heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to six substitutentsselected from R^(c). In another class of this embodiment, eachcycloalkyl and cycloheteroalkyl may be fused to phenyl or thiene. Inanother class of this embodiment, each cycloalkyl and cycloheteroalkylmay be fused to phenyl. In another class of this embodiment, eachcycloalkyl and cycloheteroalkyl ring may be fused to thiene. In anotherclass of this embodiment and subclass of these classes, thecycloheteroalkyl contains nitrogen and is attached to the B ring via abond to the nitrogen. In another class of this embodiment, R³ isunsubstituted or substituted with one to six substituents selected fromR^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to four substituents selected from R^(c).

In another embodiment of the present invention, R³ is selected from thegroup consisting of: 1) a monocyclic, bicyclic or spirocyclicC₃₋₁₂cycloalkyl ring, and 2) a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4heteroatoms independently selected from N(R^(m))_(r), O, and S, whereineach cycloalkyl ring and each cycloheteroalkyl ring may be fused to anaryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl, aryland heteroaryl is unsubstituted or substituted with one to foursubstitutents selected from R^(c). In a class of this embodiment, R³ isselected from the group consisting of: 1) a monocyclic, bicyclic orspirocyclic C₃₋₈cycloalkyl ring, and 2) a monocyclic, bicyclic orspirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkylcontains 1-4 heteroatoms independently selected from N(R^(m))_(r), O,and S, wherein each cycloalkyl ring and each cycloheteroalkyl ring maybe fused to an aryl or heteroaryl, and wherein each cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to four substitutents selected from R^(c). In another class ofthis embodiment, R³ is selected from the group consisting of: amonocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains 1-4 heteroatoms independently selectedfrom NH, O, and S, wherein each cycloalkyl and cycloheteroalkyl may befused to an aryl or heteroaryl, and wherein each cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to four substitutents selected from R^(c). In another class ofthis embodiment, each cycloalkyl and cycloheteroalkyl may be fused tophenyl or thiene. In another class of this embodiment, each cycloalkyland cycloheteroalkyl may be fused to phenyl.

In another class of this embodiment, each cycloalkyl andcycloheteroalkyl ring may be fused to thiene. In another class of thisembodiment and subclass of these classes, the cycloheteroalkyl containsnitrogen and is attached to the B ring via a bond to the nitrogen.

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring, wherein each cycloalkylmay be fused to an aryl or heteroaryl, and wherein each cycloalkyl, aryland heteroaryl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c). In a class of this embodiment, R³ isa monocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, wherein eachcycloalkyl may be fused to an aryl or heteroaryl, and wherein eachcycloalkyl, aryl and heteroaryl is unsubstituted or substituted with oneto eight substitutents selected from R^(c). In another class of thisembodiment, each cycloalkyl may be fused to phenyl or thiene. In anotherclass of this embodiment, each cycloalkyl may be fused to phenyl. Inanother class of this embodiment, each cycloalkyl may be fused tothiene. In another class of this embodiment, R³ is unsubstituted orsubstituted with one to six substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tofour substituents selected from R^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein thecycloheteroalkyl contains 1-4 heteroatoms independently selected fromN(R^(m))_(r), O, and S, wherein each cycloheteroalkyl may be fused to anaryl or heteroaryl, and wherein each cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c). In a class of this embodiment, R³ isa monocyclic, bicyclic or spirocyclic C₂₋₁₀cycloheteroalkyl ring,wherein the cycloheteroalkyl contains 1-4 heteroatoms independentlyselected from N(R^(m))_(r), O, and S, wherein each cycloheteroalkyl maybe fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl,aryl and heteroaryl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c). In another class of this embodiment,R³ is a monocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring,wherein the cycloheteroalkyl contains 1-4 heteroatoms independentlyselected from NH, O, and S, wherein each cycloheteroalkyl may be fusedto an aryl or heteroaryl, and wherein each cycloheteroalkyl, aryl andheteroaryl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c). In another class of this embodiment,each cycloheteroalkyl may be fused to phenyl or thiene. In another classof this embodiment, each cycloheteroalkyl may be fused to phenyl. Inanother class of this embodiment, each cycloheteroalkyl ring may befused to thiene. In another class of this embodiment and subclass ofthese classes, the cycloheteroalkyl contains nitrogen and is attached tothe B ring via a bond to the nitrogen. In another class of thisembodiment, R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to four substituentsselected from R^(c).

In another embodiment of the present invention, R³ is selected from thegroup consisting of: a monocyclic, bicyclic or spirocyclicC₃₋₁₂cycloalkyl ring, and a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains anitrogen and 0-3 heteroatoms independently selected from N(R^(m))_(r),O, and S, wherein each cycloalkyl and cycloheteroalkyl may be fused toan aryl or heteroaryl, and wherein each cycloalkyl, cycloheteroalkyl,aryl and heteroaryl is unsubstituted or substituted with one to sixsubstitutents selected from R^(c). In a class of this embodiment, R³ isselected from the group consisting of: a monocyclic, bicyclic orspirocyclic C₃₋₈cycloalkyl ring, and a monocyclic, bicyclic orspirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkylcontains a nitrogen and 0-3 heteroatoms independently selected fromN(R^(m))_(r), O, and S, wherein each cycloalkyl and cycloheteroalkyl maybe fused to an aryl or heteroaryl, and wherein each cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to six substitutents selected from R^(c). In another class ofthis embodiment, R³ is selected from the group consisting of: amonocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains a nitrogen and 0-3 heteroatomsindependently selected from NH, O, and S, wherein each cycloalkyl andcycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein eachcycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with one to six substitutents selected from R^(c). Inanother class of this embodiment, each cycloalkyl and cycloheteroalkylmay be fused to phenyl or thiene. In another class of this embodiment,each cycloalkyl and cycloheteroalkyl may be fused to phenyl. In anotherclass of this embodiment, each cycloalkyl and cycloheteroalkyl ring maybe fused to thiene. In another class of this embodiment and subclass ofthese classes, the cycloheteroalkyl is attached to the B ring via a bondto the R³ nitrogen. In another class of this embodiment, R³ isunsubstituted or substituted with one to four substituents selected fromR^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring, wherein each cycloalkylmay be fused to an aryl or heteroaryl, and wherein each cycloalkyl, aryland heteroaryl is unsubstituted or substituted with one to sixsubstitutents selected from R^(c). In a class of this embodiment, R³ isa monocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, wherein eachcycloalkyl may be fused to an aryl or heteroaryl, and wherein eachcycloalkyl, aryl and heteroaryl is unsubstituted or substituted with oneto six substitutents selected from R^(c). In another class of thisembodiment, each cycloalkyl may be fused to phenyl or thiene. In anotherclass of this embodiment, each cycloalkyl may be fused to phenyl. Inanother class of this embodiment, each cycloalkyl may be fused tothiene. In another class of this embodiment, R³ is unsubstituted orsubstituted with one to six substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tofour substituents selected from R^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein thecycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independentlyselected from N(R^(m))_(r), O, and S, wherein each cycloheteroalkyl maybe fused to an aryl or heteroaryl, and wherein each cycloheteroalkyl,aryl and heteroaryl is unsubstituted or substituted with one to sixsubstitutents selected from R^(c). In a class of this embodiment, R³ isa monocyclic, bicyclic or spirocyclic C₂₋₁₀cycloheteroalkyl ring,wherein the cycloheteroalkyl contains a nitrogen and 0-3 heteroatomsindependently selected from N(R^(m))_(r), O, and S, wherein eachcycloheteroalkyl may be fused to an aryl or heteroaryl, and wherein eachcycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to six substitutents selected from R^(c). In another class ofthis embodiment, R³ is a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains anitrogen and 0-3 heteroatoms independently selected from NH, O, and S,wherein each cycloheteroalkyl may be fused to an aryl or heteroaryl, andwherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted orsubstituted with one to six substitutents selected from R^(c). Inanother class of this embodiment, the cycloheteroalkyl contains anitrogen and 0-2 heteroatoms independently selected from N, O, and S. Inanother class of this embodiment, each cycloheteroalkyl may be fused tophenyl or thiene. In another class of this embodiment, eachcycloheteroalkyl may be fused to phenyl. In another class of thisembodiment, each cycloheteroalkyl ring may be fused to thiene. Inanother class of this embodiment and subclass of these classes, thecycloheteroalkyl is attached to the B ring via a bond to the R³nitrogen. In another class of this embodiment, R³ is unsubstituted orsubstituted with one to four substituents selected from R^(c).

In another embodiment of the present invention, R³ is selected from thegroup consisting of: a monocyclic, bicyclic or spirocyclicC₃₋₁₂cycloalkyl ring, and a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains 1-4heteroatoms independently selected from N(R^(m))_(r), O, and S, andwherein each cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to eight substitutents selected from R^(c). In aclass of this embodiment, R³ is selected from the group consisting of: amonocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains 1-4 heteroatoms independently selectedfrom N(R^(m))_(r), O, and S, and wherein each cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c). In another class of this embodiment,R³ is selected from the group consisting of: a monocyclic, bicyclic orspirocyclic C₃₋₈cycloalkyl ring, and a monocyclic, bicyclic orspirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkylcontains 1-4 heteroatoms independently selected from NH, O, and S, andwherein each cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to eight substitutents selected from R^(c). Inanother class of this embodiment, the cycloheteroalkyl contains nitrogenand is attached to the B ring via a bond to the R³ nitrogen. In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tosix substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to foursubstituents selected from R^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring, wherein each cycloalkyl isunsubstituted or substituted with one to eight substitutents selectedfrom R^(c). In a class of this embodiment, R³ is a monocyclic, bicyclicor spirocyclic C₃₋₈cycloalkyl ring, wherein each cycloalkyl isunsubstituted or substituted with one to eight substitutents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to six substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tofour substituents selected from R^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein thecycloheteroalkyl contains 1-4 heteroatoms independently selected fromN(R^(m))_(r), O, and S, and wherein each cycloheteroalkyl isunsubstituted or substituted with one to eight substitutents selectedfrom R^(c). In a class of this embodiment of the present invention, R³is a monocyclic, bicyclic or spirocyclic C₂₋₁₀cycloheteroalkyl ring,wherein the cycloheteroalkyl contains 1-4 heteroatoms independentlyselected from N(R^(m))_(r), O, and S, and wherein each cycloheteroalkylis unsubstituted or substituted with one to eight substitutents selectedfrom R^(c). In another class of this embodiment, R³ is a monocyclic,bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein thecycloheteroalkyl contains 1-4 heteroatoms independently selected fromNH, O, and S, and wherein each cycloheteroalkyl is unsubstituted orsubstituted with one to eight substitutents selected from R^(c). Inanother class of this embodiment, the cycloheteroalkyl contains nitrogenand is attached to the B ring via a bond to the R³ nitrogen. In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tosix substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to foursubstituents selected from R^(c).

In another embodiment of the present invention, R³ is selected from thegroup consisting of: a monocyclic, bicyclic or spirocyclicC₃₋₁₂cycloalkyl ring, and a monocyclic, bicyclic or spirocyclicC₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkyl contains anitrogen and 0-3 heteroatoms independently selected from N(R^(m))_(r),O, and S, and wherein each cycloalkyl and cycloheteroalkyl isunsubstituted or substituted with one to six substitutents selected fromR^(c). In a class of this embodiment, R³ is selected from the groupconsisting of: a monocyclic, bicyclic or spirocyclic C₃₋₈cycloalkylring, and a monocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkylring, wherein the cycloheteroalkyl contains a nitrogen and 0-3heteroatoms independently selected from N(R^(m))_(r), O, and S, andwherein each cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to six substitutents selected from R^(c). Inanother class of this embodiment, R³ is selected from the groupconsisting of: a monocyclic, bicyclic or spirocyclic C₃₋₈cycloalkylring, and a monocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkylring, wherein the cycloheteroalkyl contains a nitrogen and 0-3heteroatoms independently selected from NH, O, and S, and wherein eachcycloalkyl and cycloheteroalkyl is unsubstituted or substituted with oneto six substitutents selected from R^(c). In another class of thisembodiment, the cycloheteroalkyl contains a nitrogen and 0-2 heteroatomsindependently selected from N(R^(m))_(r), O, and S. In another class ofthis embodiment, the cycloheteroalkyl contains a nitrogen and 0-2heteroatoms independently selected from NH, O, and S. In another classof this embodiment and a subclass of this class, the cycloheteroalkyl isattached to the B ring via a bond to the R³ nitrogen. In another classof this embodiment, R³ is unsubstituted or substituted with one to foursubstituents selected from R^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring, and wherein eachcycloalkyl is unsubstituted or substituted with one to foursubstitutents selected from R^(c). In a class of this embodiment, R³ isa monocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and whereineach cycloalkyl is unsubstituted or substituted with one to foursubstitutents selected from R^(c).

In another embodiment of the present invention, R³ is a monocyclic,bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein thecycloheteroalkyl contains a nitrogen and 0-3 heteroatoms independentlyselected from N(R^(m))_(r), O, and S, and wherein each cycloheteroalkylis unsubstituted or substituted with one to four substitutents selectedfrom R^(c). In a class of this embodiment, R³ is a monocyclic, bicyclicor spirocyclic C₂₋₁₂cycloheteroalkyl ring, wherein the cycloheteroalkylcontains a nitrogen and 0-3 heteroatoms independently selected from NH,O, and S, and wherein each cycloheteroalkyl is unsubstituted orsubstituted with one to four substitutents selected from R^(c). Inanother class of this embodiment, R³ is a monocyclic, bicyclic orspirocyclic C₂₋₁₀cycloheteroalkyl ring, wherein the cycloheteroalkylcontains a nitrogen and 0-3 heteroatoms independently selected fromN(R^(m))_(r), O, and S, and wherein each cycloheteroalkyl isunsubstituted or substituted with one to four substitutents selectedfrom R^(c). In another class of this embodiment, the cycloheteroalkylcontains a nitrogen and 0-2 heteroatoms independently selected fromN(R^(m))_(r), O, and S. In another class of this embodiment, thecycloheteroalkyl contains a nitrogen and 0-2 heteroatoms independentlyselected from NH, O, and S. In another class of this embodiment and asubclass of this class, the cycloheteroalkyl is attached to the B ringvia a bond to the R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of: cyclohexane, cycloheptane, pyrrolidine, azetidine,piperidine, piperazine, azepane, morpholine, thiomorpholine, oxazepane,isoindoline, dihydroisoquinoline, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane,azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane,dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, andhexahydrofuro[3,2-b]pyrrole, wherein R³ is unsubstituted or substitutedwith one to eight substituents selected from R^(c). In a class of thisembodiment, R³ is attached to the B ring via a bond to the R³ nitrogen.In another class of this embodiment, R³ is unsubstituted or substitutedwith one to six substituents selected from R^(c). In another class ofthis embodiment, R³ is unsubstituted or substituted with one to foursubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to three substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to two substituents selected fromR^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one substituent selected from R^(c).

In another embodiment of the present invention, R³ is selected from thegroup consisting of: cyclohexane, and cycloheptane, wherein R³ isunsubstituted or substituted with one to eight substituents selectedfrom R^(c). In a class of this embodiment, R³ is attached to the B ringvia a bond to the R³ nitrogen. In another class of this embodiment, R³is unsubstituted or substituted with one to six substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to four substituents selected from R^(c). Inanother class of this embodiment, R³ is unsubstituted or substitutedwith one to three substituents selected from R^(c). In another class ofthis embodiment, R³ is unsubstituted or substituted with one to twosubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one substituent selected fromR^(c).

In another embodiment, R³ is selected from the group consisting of:pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane,morpholine, thiomorpholine, thiomorpholine dione, oxazepane,1,4-thiazepane, isoindoline, dihydroisoquinoline,tetrahydroisoquinoline, octahydro-isoindole, azabicyclo[2.2.1]heptane,oxa-azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane,diazabicyclo[3.2.1]octane, oxa-azabicyclo-[3.2.1]octane,azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.0]heptane,azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane,oxa-azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane,dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine,dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine,hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole,octahydrocyclpenta[c]pyrrole, and azatricyclo[4.3.1.13,8]undecane,wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c). In a class of this embodiment, R³ isattached to the B ring via a bond to the R³ nitrogen. In another classof this embodiment, R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to four substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to three substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with onesubstituent selected from R^(c).

In another embodiment, R³ is selected from the group consisting of:pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane,morpholine, thiomorpholine, oxazepane, 1,4-thiazepane, isoindoline,dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.1]heptane,oxa-azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane,azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]-octane,diazabicyclo[3.2.1]octane, oxa-azabicyclo[3.2.1]octane,azabicyclo[3.2.0]heptane, azaspiro[2.5]octane, azaspiro[2.6]nonane,azaspiro[3.5]nonane, oxa-azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane,dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine,dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine,hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, andazatricyclo[4.3.1.13,8]undecane, wherein R³ is unsubstituted orsubstituted with one to eight substituents selected from R^(c). In aclass of this embodiment, R³ is attached to the B ring via a bond to theR³ nitrogen. In another class of this embodiment, R³ is unsubstituted orsubstituted with one to six substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tofour substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to threesubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to two substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one substituent selected from R^(c).

In another embodiment of the present invention, R³ is selected from thegroup consisting of pyrrolidine, azetidine, piperidine, piperazine,azepane, azocane, morpholine, thiomorpholine, oxazepane, isoindoline,dihydroisoquinoline, octahydroisoindole, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]heptane, azabicyclo[4.1.0]heptane,azabicyclo[3.2.1]octane, diazabicyclo-[3.2.1]octane,azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.1]octane,azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane,oxa-azaspiro[3.5}nonane, oxa-oazaspiro[4.5]decane,dihydrothieno[3,2-c]pyridine, dihydrothiazolo[4,5-c]pyridine,dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine,hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole, andazatricyclo[4.3.1.13,8]undecane, wherein R³ is unsubstituted orsubstituted with one to eight substituents selected from R^(c). In aclass of this embodiment, R³ is unsubstituted or substituted with one tosix substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to foursubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to three substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to two substituents selected fromR^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one substituent selected from R^(c). In another classof this embodiment and a subclass of these classes, R³ is attached tothe B ring via a bond to the R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of pyrrolidine, azetidine, piperidine, piperazine,azepane, morpholine, thiomorpholine, oxazepane, isoindoline,dihydroisoquinoline, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]-heptane, azabicyclo[4.1.0]heptane,azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane,dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, andhexahydrofuro[3,2-b]pyrrole, wherein R³ is unsubstituted or substitutedwith one to eight substituents selected from R^(c). In a class of thisembodiment, R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to four substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to three substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with onesubstituent selected from R^(c). In another class of this embodiment anda subclass of these classes, R³ is attached to the B ring via a bond tothe R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of pyrrolidine, azetidine, piperidine, piperazine,azepane, morpholine, thiomorpholine, 1,4-oxazepane, isoindoline,3,4-dihydroisoqinoline, 2-azabicyclo[2.2.1]heptane,3-azabicyclo-[3.1.1]heptane, 3-azabicyclo[4.1.0]heptane,3-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.0]-heptane,6-azaspiro[2.5]octane, 5-azaspiro[2.5]octane,6,7-dihydrothieno[3,2-c]pyridine, 6,8-dihydroimidazo[1,2-a]pyrazine, and2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrole, wherein R³ is unsubstitutedor substituted with one to eight substituents selected from R^(c) In aclass of this embodiment, R³ is unsubstituted or substituted with one tosix substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to foursubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to three substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to two substituents selected fromR^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one substituent selected from R^(c). In another classof this embodiment and a subclass of these classes, R³ is attached tothe B ring via a bond to the R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of piperidine, azepane, morpholine, andazaspiro[2.5]octane, wherein R³ is unsubstituted or substituted with oneto eight substituents selected from R^(c). In a class of thisembodiment, R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to four substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to three substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with onesubstituent selected from R^(c). In another class of this embodiment anda subclass of these classes, R³ is attached to the B ring via a bond tothe R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of piperidine, azepane, morpholine, and6-azaspiro[2.5]octane, wherein R³ is unsubstituted or substituted withone to eight substituents selected from R^(c). In a class of thisembodiment, R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to four substituentsselected from R^(c). In another class of this embodiment, R³ isunsubstituted or substituted with one to three substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with onesubstituent selected from R^(c). In another class of this embodiment anda subclass of these classes, R³ is attached to the B ring via a bond tothe R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of piperidine, azepane, and morpholine, wherein R³ isunsubstituted or substituted with one to eight substituents selectedfrom R^(c). In a class of this embodiment, R³ is unsubstituted orsubstituted with one to six substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tofour substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to threesubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to two substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one substituent selected from R^(c). In another classof this embodiment and a subclass of these classes, R³ is attached tothe B ring via a bond to the R³ nitrogen.

In another embodiment of the present invention, R³ is selected from thegroup consisting of: piperidine, and azepane, wherein R³ isunsubstituted or substituted with one to eight substituents selectedfrom R^(c). In a class of this embodiment, R³ is unsubstituted orsubstituted with one to six substituents selected from R^(c). In anotherclass of this embodiment, R³ is unsubstituted or substituted with one tofour substituents selected from R^(c). In another class of thisembodiment, R³ is unsubstituted or substituted with one to threesubstituents selected from R^(c). In another class of this embodiment,R³ is unsubstituted or substituted with one to two substituents selectedfrom R^(c). In another class of this embodiment, R³ is unsubstituted orsubstituted with one substituent selected from R^(c). In another classof this embodiment and a subclass of these classes, R³ is attached tothe B ring via a bond to the R³ nitrogen. In another class of thisembodiment and a subclass of these classes, piperidine and azepane areeach individually attached to the B ring via a bond to the piperidine orazepane nitrogen.

In another embodiment of the present invention, R³ is piperidine,wherein piperidine is unsubstituted or substituted with one to eightsubstituents selected from R^(c). In a class of this embodiment,piperidine is unsubstituted or substituted with one to six substituentsselected from R^(c). In another class of this embodiment, piperidine isunsubstituted or substituted with one to four substituents selected fromR^(c). In another class of this embodiment, piperidine is unsubstitutedor substituted with one to three substituents selected from R^(c). Inanother class of this embodiment, piperidine is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, piperidine is unsubstituted or substitutedwith one substituent selected from R^(c). In another class of thisembodiment and a subclass of these classes, piperidine is attached tothe B ring via a bond to the R³ nitrogen. In another class of thisembodiment and a subclass of these classes, piperidine is attached tothe B ring via a bond to the piperidine nitrogen.

In another embodiment of the present invention, R³ is azepane, whereinazepane is unsubstituted or substituted with one to eight substituentsselected from R^(c). In a class of this embodiment, azepane isunsubstituted or substituted with one to six substituents selected fromR^(c). In another class of this embodiment, azepane is unsubstituted orsubstituted with one to four substituents selected from R^(c). Inanother class of this embodiment, azepane is unsubstituted orsubstituted with one to three substituents selected from R^(c). Inanother class of this embodiment, azepane is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, azepane is unsubstituted or substituted withone substituent selected from R^(c). In another class of this embodimentand a subclass of these classes, azepane is attached to the B ring via abond to the R³ nitrogen. In another class of this embodiment and asubclass of these classes, azepane is attached to the B ring via a bondto the azepane nitrogen.

In another embodiment of the present invention, R³ is morpholine,wherein morpholine is unsubstituted or substituted with one to eightsubstituents selected from R^(c). In a class of this embodiment,morpholine is unsubstituted or substituted with one to six substituentsselected from R^(c). In another class of this embodiment, morpholine isunsubstituted or substituted with one to four substituents selected fromR^(c). In another class of this embodiment, morpholine is unsubstitutedor substituted with one to three substituents selected from R^(c). Inanother class of this embodiment, morpholine is unsubstituted orsubstituted with one to two substituents selected from R^(c). In anotherclass of this embodiment, morpholine is unsubstituted or substitutedwith one substituent selected from R^(c). In another class of thisembodiment and a subclass of these classes, morpholine is attached tothe B ring via a bond to the R³ nitrogen. In another class of thisembodiment and a subclass of these classes, morpholine is attached tothe B ring via a bond to the morpholine nitrogen.

In another embodiment of the present invention, each R^(a) is selectedfrom the group consisting of: —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —OH,oxo, —CN, —C₃₋₆cycloalkyl, and —C₂₋₅cycloheteroalkyl, wherein eachalkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substitutedwith one to six substituents selected from halogen, OH, NH₂,NH(C₁₋₆alkyl) and N(C₁₋₆alkyl)₂; In a class of this embodiment, R^(a) issubstituted with a halogen selected from: F, Br, and Cl. In a subclassof this class, the halogen is F or Cl. In another subclass of thisclass, the halogen is Cl. In another subclass of this class, the halogenis F.

In another embodiment, each R^(a) is selected from the group consistingof: —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —OH, oxo, —CN, and—C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted orsubstituted with one to six substituents selected from halogen, OH, NH₂,NH(C₁₋₆alkyl) and N(C₁₋₆alkyl)₂. In a class of this embodiment, R^(a) issubstituted with a halogen selected from: F, Br, and Cl. In a subclassof this class, the halogen is F or Cl. In another subclass of thisclass, the halogen is Cl. In another subclass of this class, the halogenis F.

In another embodiment, each R^(a) is selected from the group consistingof: —C₁₋₆ alkyl, —OC₁₋₆alkyl, halogen, —OH, oxo, and CN, wherein eachalkyl is unsubstituted or substituted with one to six substituentsselected from halogen, OH, NH₂, NH(C₁₋₆alkyl) and N(C₁₋₆alkyl)₂. In aclass of this embodiment, R^(a) is substituted with a halogen selectedfrom: F, Br, and Cl. In a subclass of this class, the halogen is F orCl. In another subclass of this class, the halogen is Cl. In anothersubclass of this class, the halogen is F.

In another embodiment, each R^(a) is selected from the group consistingof: —C₁₋₆ alkyl, halogen, —OH, oxo, and CN, wherein each alkyl isunsubstituted or substituted with one to six substituents selected fromhalogen, OH, NH₂, NH(C₁₋₆alkyl) and N(C₁₋₆alkyl)₂. In a class of thisembodiment, R^(a) is substituted with a halogen selected from: F, Br,and Cl. In a subclass of this class, the halogen is F or Cl. In anothersubclass of this class, the halogen is Cl. In another subclass of thisclass, the halogen is F.

In another embodiment, each R^(a) is selected from the group consistingof: —C₁₋₆alkyl, halogen, —OH, and oxo, wherein each alkyl isunsubstituted or substituted with one to six substituents selected fromhalogen, OH, NH₂, NH(C₁₋₆alkyl) and N(C₁₋₆alkyl)₂. In a class of thisembodiment, R^(a) is substituted with a halogen selected from: F, Br,and Cl. In a subclass of this class, the halogen is F or Cl. In anothersubclass of this class, the halogen is Cl. In another subclass of thisclass, the halogen is F.

In another embodiment, each R^(a) is selected from the group consistingof: —C₁₋₆alkyl, halogen, —OH, and oxo. In a class of this embodiment,each R^(a) is selected from the group consisting of: CH₃, halogen, —OH,and oxo.

In another embodiment, each R^(a) is selected from the group consistingof: —C₁₋₆alkyl and halogen. In another embodiment, each R^(a) isselected from the group consisting of: CH₃ and halogen.

In another embodiment, each R^(a) is halogen.

In another embodiment, R^(a) is —C₁₋₆alkyl, wherein alkyl is substitutedwith a halogen selected from: F, Br, and Cl. In a subclass of thisclass, the halogen is F or Cl. In another subclass of this class, thehalogen is Cl. In another subclass of this class, the halogen is F.

In another embodiment, R^(a) is —C₁₋₆alkyl. In a class of thisembodiment, R^(a) is CH₃.

In another embodiment of the present invention, each each R^(b) isindependently selected from the group consisting of: —CF₃, —CF₂CF₃;—CHF₂, —OCHF₂, —OCH₂CF₃, —OCF₃, CN, halogen, —Si(C₁₋₆alkyl)₃,—C₁₋₆alkyl-O—R^(k), —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,—C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl, —C₂₋₆alkenyl-C₃₋₆cycloalkyl,—C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl, —C₂₋₆alkenyl-aryl,—C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₆cycloalkyl, —C₂₋₆alkynylcycloheteroalkyl, —C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl, NO₂, —OH,—(CH₂)_(p)—OC₁₋₆alkyl, —(CH₂)_(p)—OC₂₋₆alkenyl, —(CH₂)_(p)—OC₂₋₆alkynyl,—(CH₂)_(p)—OC₃₋₆cycloalkyl, —(CH₂)_(p)—OC₂₋₆heterocycloalkyl,—(CH₂)_(p)—O-aryl, —(CH₂)_(p)—O-heteroaryl, —OC₁₋₆alkyl-C₃₋₆cycloalkyl,—OC₁₋₆alkyl-C₂₋₆heterocycloalkyl, —OC₁₋₆alkyl-aryl,—OC₁₋₆alkyl-heteroaryl, —S(O)_(m)R^(k), —C₁₋₆alkyl-S(O)_(m)R^(k),—C(O)R^(k), —N(R^(i))₂, and —NR^(i)R^(k), wherein each R^(b) isunsubstituted or substituted with one to five substituents selected fromR^(f).

In another embodiment, each R^(b) is independently selected from thegroup consisting of: —CF₃, —CHF₂, —OCHF₂, —OCH₂CF₃, —OCF₃, CN, halogen,—Si(C₁₋₆alkyl)₃, —C₁₋₆alkyl, —OC₁₋₆alkyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₂₋₆alkyl-C₃₋₆cycloalkyl,—C₂₋₆alkynyl-C₃₋₆cycloalkyl, and heteroaryl, wherein each R^(b) isunsubstituted or substituted with one to five substituents selected fromR^(f). In a class of this embodiment, each R^(b) is independentlyselected from the group consisting of: —CF₃, —CHF₂, —OCHF₂, —OCH₂CF₃,—OCF₃, CN, F, Cl, Br, —Si(CH₃)₃, —CH₃, —C(CH₃)₃, —OCH₃, cyclopropyl,cyclobutyl, piperidine, —CH₂-cyclopropyl, —C₂alkynyl-cyclopropyl, andpyrazole, wherein each R^(b) is unsubstituted or substituted with one tofive substituents selected from R^(f).

In another embodiment, each R^(b) is independently selected from thegroup consisting of: —CF₃, —CHF₂, —OCHF₂, —OCH₂CF₃, —OCF₃, CN, halogen,—C₁₋₆alkyl, —OC₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,—C₂₋₆alkyl-C₃₋₆cycloalkyl, —C₂₋₆alkynyl-C₃₋₆cycloalkyl, and heteroaryl,wherein each R^(b) is unsubstituted or substituted with one to fivesubstituents selected from R^(f) In a class of this embodiment, eachR^(b) is independently selected from the group consisting of: —CF₃,—CHF₂, —OCHF₂, —OCH₂CF₃, —OCF₃, CN, F, Cl, Br, —CH₃, —C(CH₃)₃, —OCH₃,cyclopropyl, cyclobutyl, piperidine, —CH₂-cyclopropyl,—C₂alkynyl-cyclopropyl, and pyrazole, wherein each R^(b) isunsubstituted or substituted with one to five substituents selected fromR^(f).

In another embodiment, each R^(b) is independently selected from thegroup consisting of:—CF₃, —CHF₂, —OCHF₂, CN, halogen, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, and —C₂₋₆alkyl-C₃₋₆cycloalkyl, wherein each R^(b) isunsubstituted or substituted with one to five substituents selected fromR^(f). In a class of this embodiment, each R^(b) is independentlyselected from the group consisting of: —CF₃, —CHF₂, —OCHF₂, CN, F, Cl,Br, —CH₃, —C(CH₃)₃, cyclopropyl, cyclobutyl, and —CH₂-cyclopropyl,wherein each R^(b) is unsubstituted or substituted with one to fivesubstituents selected from R^(f).

In another embodiment, each R^(b) is independently selected from thegroup consisting of: —CF₃, —CHF₂, halogen, —C₁₋₆alkyl, and—C₃₋₆cycloalkyl, wherein each R^(b) is unsubstituted or substituted withone to five substituents selected from R^(f). In a class of thisembodiment, each R^(b) is independently selected from the groupconsisting of: —CF₃, —CHF₂, F, Cl, Br, —CH₃, —C(CH₃)₃, cyclopropyl, andcyclobutyl, wherein each R^(b) is unsubstituted or substituted with oneto five substituents selected from R^(f) In another class of thisembodiment, each R^(b) is independently selected from the groupconsisting of: —CF₃, —CHF₂, F, Cl, —CH₃, cyclopropyl and cyclobutyl,wherein each R^(b) is unsubstituted or substituted with one to fivesubstituents selected from R^(f).

In another embodiment, each R^(b) is independently selected from thegroup consisting of: —CF₃, and —C₁₋₆alkyl, wherein each R^(b) isunsubstituted or substituted with one to five substituents selected fromR^(f) In a class of this embodiment, each R^(b) is independentlyselected from the group consisting of: —CF₃, and —C₁₋₆alkyl. In anotherclass of this embodiment, each R^(b) is independently selected from thegroup consisting of: —CF₃, and —CH₃, wherein —CH₃ is unsubstituted orsubstituted with one to five substituents selected from R^(f) In a classof this embodiment, each R^(b) is independently selected from the groupconsisting of: —CF₃, and —CH₃.

In another class of this embodiment, each R^(b) is —CH₃. In anotherclass of this embodiment, each R^(b) is CF₃.

In another embodiment of the present invention, each R^(c) isindependently selected from the group consisting of: —CF₃, —CH₂CF₃,—CHF₂, —OCHF₂, —OCF₃, CN, oxo, —OH, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,—C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl, —C₁₋₆alkenyl-C₃₋₆cycloalkyl,—C₁₋₆alkenyl-aryl, —C₁₋₆alkenyl heteroaryl,—C₁₋₆alkenyl-C₂₋₆cycloheteroalkyl, —C₂₋₆alkynyl-C₃₋₆cycloalkyl,—C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl, —C₂₋₆alkynyl-aryl, —C₂₋₆alkynylheteroaryl, —OC₁₋₆alkyl, —OC₂₋₆ alkenyl, —OC₂₋₆ alkynyl, —OC₃₋₆cycloalkyl, —OC₂₋₆ heterocycloalkyl, —O-aryl, —O-heteroaryl,—OC₁₋₆alkyl-cycloalkyl, —OC₁₋₆alkyl-cycloheteroalkyl, —OC₁₋₆alkyl-aryl,—OC₁₋₆ alkyl-heteroaryl, —S(O)_(m)R^(L), —S(O)R^(L), —S—R^(L),—C₁₋₆alkyl-S(O)_(m)R^(L), —C(O)R^(L), —C(O)C₁₋₆alkyl-R^(L), —OC(O)R^(L),—CO₂R^(L), aryl, and heteroaryl, wherein each R^(c) is unsubstituted orsubstituted with one to five substituents selected from R^(g).

In another embodiment, each R^(c) is independently selected from thegroup consisting of: —CF₃, —CH₂CF₃, —CHF₂, —OCF₃, CN, halogen,—C₁₋₆alkyl, oxo, —OH, —C₁₋₆alkyl-OH, —O-aryl, —O-heteroaryl, aryl,heteroaryl, —C₁₋₆alkyl-aryl, and —C₁₋₆alkyl-heteroaryl, wherein eachR^(c) is unsubstituted or substituted with one to five substituentsselected from R^(g). In a class of this embodiment, each R^(c) isindependently selected from the group consisting of: —CF₃, —CH₂CF₃,—CHF₂, —OCF₃, CN, F, Cl, —CH₃, —CH₂CH₃, oxo, —OH, —CH₂OH, —O-phenyl,phenyl, pyrazole, and —CH₂-phenyl, wherein each R^(c) is unsubstitutedor substituted with one to five substituents selected from R^(g).

In another embodiment, each R^(c) is independently selected from thegroup consisting of: —CF₃, —CH₂CF₃, —CHF₂, —OCF₃, CN, halogen,—C₁₋₆alkyl, oxo, —OH, —C₁₋₆alkyl-OH, —O-aryl, aryl, heteroaryl, and—C₁₋₆alkyl-aryl, wherein each R^(c) is unsubstituted or substituted withone to five substituents selected from R^(g). In a class of thisembodiment, each R^(c) is independently selected from the groupconsisting of: —CF₃, —CH₂CF₃, —CHF₂, —OCF₃, CN, F, Cl, —CH₃, —CH₂CH₃,oxo, —OH, —CH₂OH, —O-phenyl, phenyl, pyrazole, and —CH₂-phenyl, whereineach R^(c) is unsubstituted or substituted with one to five substituentsselected from R^(g).

In another embodiment, each R^(c) is independently selected from thegroup consisting of: —CF₃, halogen, and —C₁₋₆alkyl, wherein each R^(c)is unsubstituted or substituted with one to five substituents selectedfrom R^(g). In a class of this embodiment, each R^(c) is independentlyselected from the group consisting of: —CF₃, F, Cl, —CH₃ and —CH₂CH₃. Inanother class of this embodiment, each R^(c) is independently selectedfrom the group consisting of: —CF₃, F, and —CH₃.

In another embodiment, each R^(c) is independently selected from thegroup consisting of: halogen and —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to five substituents selected fromR^(g). In a class of this embodiment, each R^(c) is independentlyselected from the group consisting of: halogen and —C₁₋₆alkyl, whereineach alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(g). In another class of this embodiment,each R^(c) is independently selected from the group consisting of:halogen and —C₁₋₆alkyl. In another class of this embodiment, each R^(c)is independently selected from the group consisting of: F and —CH₃.

In another embodiment, each R^(c) is —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to five substituents selected fromR^(g). In a class of this embodiment, each R^(c) is —C₁₋₆alkyl, whereineach alkyl is unsubstituted or substituted with one to threesubstituents selected from R^(g). In another class of this embodiment,each R^(c) is —C₁₋₆alkyl. In another class of this embodiment, eachR^(c) is —CH₃.

In another embodiment, each R^(c) is halogen. In a class of thisembodiment, each R^(c) is F.

In another embodiment of the present invention, R^(d) is independentlyselected from the group consisting of: hydrogen, halogen, OH, oxo,—C₁₋₆alkyl, —OC₁₋₆alkyl, NH₂, NH(C₁₋₆alkyl), and N(C₁₋₆alkyl)₂. Inanother embodiment of the present invention, R^(d) is independentlyselected from the group consisting of: halogen, OH, oxo, —C₁₋₆alkyl,—OC₁₋₆alkyl, NH₂, NH(C₁₋₆alkyl), and N(C₁₋₆alkyl)₂.

In another embodiment of the present invention, R^(d) is independentlyselected from the group consisting of: hydrogen, halogen, OH, oxo,—C₁₋₆alkyl, —OC₁₋₆alkyl, and NH₂. In another embodiment of the presentinvention, R^(d) is independently selected from the group consisting of:halogen, OH, oxo, —C₁₋₆alkyl, —OC₁₋₆alkyl, and NH₂.

In another embodiment, R^(d) is independently selected from the groupconsisting of: hydrogen, halogen, —OH, N(R^(g))₂, and C₁₋₆alkyl. In aclass of this embodiment, R^(d) is independently selected from the groupconsisting of: hydrogen, F, —OH, NH₂, and CH₃.

In another embodiment, R^(d) is independently selected from the groupconsisting of: hydrogen, halogen, —OH, oxo, N(R^(g))₂, and C₁₋₆alkyl. Ina class of this embodiment, R^(d) is independently selected from thegroup consisting of: hydrogen, F, —OH, NH₂, and CH₃. In anotherembodiment, R^(d) is independently selected from the group consistingof: halogen, —OH, oxo, N(R^(g))₂, and C₁₋₆alkyl. In a class of thisembodiment, R^(d) is independently selected from the group consistingof: F, —OH, NH₂, and CH₃.

In another embodiment, R^(d) is independently selected from the groupconsisting of: halogen, —OH, N(R^(g))₂, and C₁₋₆alkyl. In a class ofthis embodiment, R^(d) is independently selected from the groupconsisting of: F, —OH, NH₂, and CH₃.

In another embodiment, R^(d) is independently selected from the groupconsisting of: hydrogen, halogen, and C₁₋₆alkyl. In a class of thisembodiment, R^(d) is independently selected from the group consistingof: hydrogen, F and CH₃. In another embodiment, R^(d) is independentlyselected from the group consisting of: halogen, and C₁₋₆alkyl. In aclass of this embodiment, R^(d) is independently selected from the groupconsisting of: F and CH₃.

In another embodiment of the present invention, each R^(e) isindependently selected from the group consisting of: hydrogen,—C₁₋₆alkyl, and —C₂₋₆alkenyl. In another embodiment, R^(d) isindependently selected from the group consisting of: —OH, and N(R⁹)₂. Ina class of this embodiment, R^(d) is independently selected from thegroup consisting of: —OH, and NH₂. In another class of this embodiment,R^(d) is —OH. In another class of this embodiment, R^(d) is NH₂.

In another embodiment of the present invention, each R^(e) isindependently selected from the group consisting of: hydrogen, and—C₁₋₆alkyl. In a class of this embodiment, R^(e) is hydrogen. In anotherclass of this embodiment, R^(e) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl,—OC₃₋₆cycloalkyl, —OC₂₋₆cycloheteroalkyl, CN, —NH₂, —NH(C₁₋₆alkyl),—NH(C₃₋₆cycloalkyl), —NH(C₂₋₆cycloheteroalkyl), —N(C₁₋₆alkyl)₂,—N(C₃₋₆cycloalkyl)₂, and —N(C₂₋₆cycloheteroalkyl)₂,

wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl,—OC₃₋₆cycloalkyl, —OC₂₋₆cycloheteroalkyl, CN, —NH₂, —NH(C₁₋₆alkyl), and—N(C₁₋₆alkyl)₂, wherein each alkyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, CN,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂, wherein each alkyl isunsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, andCN, wherein each alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, cyano, and—S(O)₂CH₃.

In another embodiment of the present invention, each R^(f) is selectedfrom the group consisting of: halogen, —C₁₋₆alkyl, and —OH, wherein eachalkyl is unsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, cyano, and —S(O)₂CH₃. In aclass of this embodiment, each R^(f) is selected from the groupconsisting of: F, —CH₃, and —OH.

In another embodiment of the present invention, each R^(f) is halogen.In a class of this embodiment, R^(f) is F.

In another embodiment of the present invention, each R^(f) is—C₁₋₆alkyl, wherein each alkyl is unsubstituted or substituted with oneto three substituents independently selected from: —OH, halogen, cyano,and —S(O)₂CH₃. In a class of this embodiment, each R^(f) is —C₁₋₆alkyl.In a subclass of this class, R^(f) is —CH₃.

In another embodiment of the present invention, each R^(f) is —OH.

In another embodiment of the present invention, each R^(g) is selectedfrom the group consisting of: halogen, C₁₋₆alkyl, —OH, —OC₁₋₆alkyl,—S(O)_(m)—C₁₋₆alkyl, —CN, —CF₃, —OCHF₂, and —OCF₃, wherein each alkyl isunsubstituted or substituted with one to three substituentsindependently selected from: —OH, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(g) is selectedfrom the group consisting of: halogen, C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, —CN,—CF₃, —OCHF₂, and —OCF₃, wherein each alkyl is unsubstituted orsubstituted with one to three substituents independently selected from:—OH, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(g) is selectedfrom the group consisting of: halogen, C₁₋₆alkyl, —OH, —CN, —CF₃,wherein each alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, cyano, and—S(O)₂CH₃.

In another embodiment of the present invention, each R^(g) is selectedfrom the group consisting of: halogen, —OH, —CN, and —CF₃. In a class ofthis embodiment, each R^(g) is selected from the group consisting of: F,—OH, —CN, and —CF₃.

In another embodiment of the present invention, each R^(h) isindependently selected from the group consisting of: hydrogen, and—C₁₋₆alkyl. In a class of this embodiment, R^(h) is hydrogen. In anotherclass of this embodiment, R^(h) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(i) isindependently selected from the group consisting of: hydrogen, and—C₁₋₆alkyl. In a class of this embodiment, R^(i) is hydrogen. In anotherclass of this embodiment, R^(i) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(g) halogen. In aclass of this embodiment, each R^(g) is F.

In another embodiment of the present invention, each R^(j) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, aryl, and heteroaryl, wherein each alkyl,alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(j) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(j) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃. Inanother embodiment of the present invention, each R is selected from thegroup consisting of: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, cycloalkyl, andcycloheteroalkyl.

In another embodiment of the present invention, each R^(j) is—C₁₋₆alkyl, wherein each alkyl, is unsubstituted or substituted with oneto three substituents independently selected from: —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and—S(O)₂CH₃. In a class of this embodiment, each R^(j) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(k) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, and heteroaryl, whereineach alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroarylis unsubstituted or substituted with one to three substituentsindependently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(k) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(k) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(k) is—C₁₋₆alkyl, wherein each alkyl, is unsubstituted or substituted with oneto three substituents independently selected from: —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and—S(O)₂CH₃. In a class of this embodiment, each R^(k) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(L) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, aryl, and heteroaryl, wherein each alkyl,alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(L) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl,and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(L) is selectedfrom the group consisting of: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH₃.

In another embodiment of the present invention, each R^(L) is—C₁₋₆alkyl, wherein each alkyl, is unsubstituted or substituted with oneto three substituents independently selected from: —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and—S(O)₂CH₃. In a class of this embodiment, each R^(L) is —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(m) isindependently selected from the group consisting of: hydrogen, and—C₁₋₆alkyl. In a class of this embodiment, R^(m) is hydrogen. In anotherclass of this embodiment, R^(m) is —C₁₋₆alkyl.

In another embodiment of the present invention, n is 0, 1, 2, 3 or 4. Ina class of this embodiment, n is 0, 1, 2 or 3. In another class of thisembodiment, n is 0, 1 or 2. In a class of this embodiment, n is 0 or 1.In a class of this embodiment, n is 1, 2, 3 or 4. In another class ofthis embodiment, n is 1, 2 or 3. In another class of this embodiment, nis 1 or 2. In another class of this embodiment, n is 0. In another classof this embodiment, n is 1. In another class of this embodiment, n is 2.In another class of this embodiment, n is 3. In another class of thisembodiment, n is 4.

In another embodiment of the present invention, m is 0, 1 or 2. In aclass of this embodiment, m is 0 or 1. In another class of thisembodiment, m is 1 or 2. In another class of this embodiment, m is 0. Inanother class of this embodiment, m is 1. In another class of thisembodiment, m is 2.

In another embodiment of the present invention, p is 0, 1, 2, 3 or 4. Ina class of this embodiment, p is 0, 1, 2 or 3. In another class of thisembodiment, p is 0, 1 or 2. In a class of this embodiment, p is 0 or 1.In a class of this embodiment, p is 1, 2, 3 or 4. In another class ofthis embodiment, p is 1, 2 or 3. In another class of this embodiment, pis 1 or 2. In another class of this embodiment, p is 0. In another classof this embodiment, p is 1. In another class of this embodiment, p is 2.In another class of this embodiment, p is 3. In another class of thisembodiment, p is 4.

In another embodiment of the present invention, q is 0 or 1. In anotherclass of this embodiment, q is 0. In another class of this embodiment, qis 1.

In another embodiment of the present invention, r is 0 or 1. In anotherclass of this embodiment, r is 0. In another class of this embodiment, ris 1.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

or a pharmaceutically acceptable salt thereof. In a class of thisembodiment, A is pyridine. In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

or a pharmaceutically acceptable salt thereof. In a class of thisembodiment, A is pyridine. In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is:

In another class of this embodiment, A is:

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof. In a class of thisembodiment, A is pyridine. In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is

In another class of this embodiment, A is:

The compound of structural formula I, includes the compounds ofstructural formulas Ia, Ib, and 1c, and pharmaceutically acceptablesalts, hydrates and solvates thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is selected from the group consisting of:

(1) pyridine,

(2) pyrimidine,

(3) pyrazine,

(4) indazole,

(5) imidazo[1,2-a]pyridine,

(6) pyrrolo[3,2-c]pyridine,

(7) pyrrolo[2,3-b]pyridine,

(8) pyrazole,

(9) thiophene, and

(10) 1,2,4-oxadiazole,

wherein A is unsubstituted or substituted with one to five substituentsselected from R^(a);

B is selected from the group consisting of:

(1) pyrazine,

(2) pyridine,

(3) pyrimidine, and

(4) pyridazine,

wherein each B is unsubstituted or substituted with one to threesubstituents selected from R^(b);

R¹ is selected from the group consisting of:

(1) —SO₃H,

(2) —SO₂NH₂,

(3) —SO₂C₁₋₆alkyl-NH₂,

(4) —SO₂NH—C₁₋₆alkyl,

(5) —SO₂C₁₋₆alkyl,

(6) —SO₂C₃₋₆cycloalkyl,

(7) —C(O)NH₂,

(8) —CO₂H,

(9) —CN,

(10) halogen,

(11) —OH,

(12) —OC₁₋₆alkyl,

(13) —C₁₋₆alkyl,

(14) —C₁₋₆alkyl-OH, and

(15) CF₃,

wherein each alkyl, and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(d);

R² is hydrogen;

R³ is selected from the group consisting of:

(1) cyclohexane,

(2) cycloheptane,

(3) pyrrolidine,

(4) azetidine,

(5) piperidine,

(6) piperazine,

(7) azepane,

(8) morpholine,

(9) thiomorpholine,

(10) oxazepane,

(11) isoindoline,

(12) dihydroisoquinoline,

(13) azabicyclo[2.2.1]heptane,

(14) azabicyclo[3.1.1]heptane,

(15) azabicyclo[4.1.0]heptane,

(16) azabicyclo[3.2.1]octane,

(17) azabicyclo[3.2.0]heptane,

(18) azaspiro[2.5]octane,

(19) dihydrothieno[3,2-c]pyridine,

(20) dihydroimidazo[1,2-a]pyrazine, and

(21) hexahydrofuro[3,2-b]pyrrole,

wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c);

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is selected from the group consisting of:

(1) pyridine,

(2) pyrimidine,

(3) pyrazine,

(4) indazole,

(5) imidazo[1,2-a]pyridine,

(6) pyrrolo[3,2-c]pyridine,

(7) pyrrolo[2,3-b]pyridine,

(8) pyrazole,

(9) thiophene, and

(10) 1,2,4-oxadiazole,

wherein A is unsubstituted or substituted with one to five substituentsselected from R^(a);

B is selected from the group consisting of:

(1) pyridine,

(2) pyrimidine, and

(3) pyridazine,

wherein each B is unsubstituted or substituted with one to threesubstituents selected from R^(b);

R¹ is selected from the group consisting of:

(1) —SO₃H,

(2) —SO₂NH₂,

(3) —SO₂C₁₋₆alkyl-NH₂,

(4) —SO₂NH—C₁₋₆alkyl,

(5) —SO₂C₁₋₆alkyl,

(6) —SO₂C₃₋₆cycloalkyl,

(7) —C(O)NH₂,

(8) —CO₂H,

(9) —CN,

(10) halogen,

(11) —OH,

(12) —OC₁₋₆alkyl,

(13) —C₁₋₆alkyl,

(14) —C₁₋₆alkyl-OH, and

(15) CF₃,

wherein each alkyl, and cycloalkyl is unsubstituted or substituted withone to three substituents selected from R^(d);

R² is hydrogen;

R³ is selected from the group consisting of:

(1) pyrrolidine,

(2) azetidine,

(3) piperidine,

(4) piperazine,

(5) azepane,

(6) morpholine,

(7) thiomorpholine,

(8) oxazepane,

(9) isoindoline,

(10) dihydroisoquinoline,

(11) azabicyclo[2.2.1]heptane,

(12) azabicyclo[3.1.1]heptane,

(13) azabicyclo[4.1.0]heptane,

(14) azabicyclo[3.2.1]octane,

(15) azabicyclo[3.2.0]heptane,

(16) azaspiro[2.5]octane,

(17) dihydrothieno[3,2-c]pyridine,

(18) dihydroimidazo[1,2-a]pyrazine, and

(19) hexahydrofuro[3,2-b]pyrrole,

wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c);

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is pyridine, wherein pyridine is unsubstituted or substituted with oneto three substituents selected from R^(a);

B is pyridine, wherein pyridine is unsubstituted or substituted with oneto three substituents selected from R^(b);

R¹ is selected from the group consisting of:

(1) —SO₂NH₂,

(2) —C(O)NH₂, and

(3) —OH;

R² is hydrogen;

R³ is selected from the group consisting of:

(1) piperidine,

(2) azepane, and

(3) morpholine,

wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c);

or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as inhibitors of Na_(v)1.8 channel activityare the following compounds:

-   1)    2-(4,4-difluoropiperidin-1-yl)-N-(6-sulfamoylpyrazin-2-yl)-5-(trifluoromethyl)-nicotinamide;-   2)    2-(4,4-difluoropiperidin-1-yl)-N-(4-hydroxypyrimidin-2-yl)-5-(trifluoromethyl)-nicotinamide;-   3)    5-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinic    acid;-   4)    4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinic    acid;-   5)    N-(6-cyanopyridin-3-yl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide;-   6)    2-(azepan-1-yl)-N-(5-(methylsulfonyl)pyridin-3-yl)-5-(trifluoromethyl)nicotinamide;-   7)    2-(3-(hydroxymethyl)piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   8)    2-(azepan-1-yl)-N-(5-carbamoylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide;-   9)    2-(4,4-difluoro-1-piperidyl)-6-methyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   10)    5-chloro-2-(4,4-difluoro-1-piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   11)    6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(5-sulfamoylpyridin-3-yl)nicotinamide;-   12)    5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   13)    2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   14)    5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   15)    5-cyclobutyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   16)    5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1l-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   17)    2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   18)    6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   19)    2-(4,4-difluoroazepan-1-yl)-5,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   20)    5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide;-   21)    5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;-   22)    6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   23)    5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;-   24)    6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   25)    2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   26)    2-(4,4-difluoropiperidin-1l-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   27)    5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-nicotinamide;-   28)    2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   29)    2-(4,4-Dichloropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   30)    2-(4,4-difluoroazepan-1-yl)-N-[1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;-   31)    5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-[1-(methylsulfonyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide;-   32)    5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-[1-(methylsulfonyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide;-   33)    N-{1-[(2-aminoethyl)sulfonyl]-1H-pyrazol-4-yl}-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylpyridine-3-carboxamide;-   34)    2-(4,4-difluoroazepan-1-yl)-N-[1-(methylsulfonyl)-1H-indazol-3-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;-   35)    2-(4,4-difluoroazepan-1-yl)-N-[1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;-   36)    N-[1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl]-2-(4,4-difluoroazepan-1-yl)-5-(trifluoro-methyl)pyridine-3-carboxamide;-   37)    N-[5-cyclopropyl-1-(methylsulfonyl)-1H-pyrazol-4-yl]-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   38)    2-cyclopropyl-4-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrimidine-5-carboxamide;-   39)    6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyridazine-4-carboxamide;-   40)    6-methyl-N-(2-sulfamoylpyridin-4-yl)-2-(3,4,4-trifluoroazepan-1-yl)nicotinamide;-   41)    5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;-   42)    N-[2-(tert-butylsulfamoyl)pyridin-4-yl]-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methoxy-pyridine-3-carboxamide;-   43)    5-cyano-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-nicotinamide;-   44)    5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;-   45)    2-(azepan-1-yl)-N-(3-cyano-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   46)    5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   47)    (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;-   48)    (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)-nicotinamide;-   49)    (R)-2-(4,4-dichloro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;-   50)    (S)-2-(4,4-dichloro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;-   51)    2-(4,4-Dichloroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   52)    2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   53)    5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-6-methyl-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;-   54)    (S)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   55)    (R)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   56)    (S)-2-(3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   57)    (R)-2-(3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   58) N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[(1S,5    S)-1-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl]pyridine-3-carboxamide;-   59)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[(1R,5R)-1-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl]pyridine-3-carboxamide;-   60)    N-(2-sulfamoylpyridin-4-yl)-2-((1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl)-5-(trifluoromethyl)nicotinamide;-   61)    2-[(1S,6S)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   62)    2-[((1R,6R)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   63)    2-((1R,5S)-8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   64)    2-((1R,5S)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   65)    2-((1S,5R)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   66)    (R)-2-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   67)    (S)-2-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   68)    2-((1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   69)    2-((1S,6S)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   70)    2-((1R,6R)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   71)    2-[((1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   72)    2-[(1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   73)    (R)-2-(4,4-difluoro-2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   74)    (S)-2-(4,4-difluoro-2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   75)    2-((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   76)    2-((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   77)    2-[(3S,4S)-4-hydroxy-3-methyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   78)    2-[(3S,4r,5R)-4-hydroxy-3,5-dimethyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;-   79)    2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;-   80)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide;-   81)    2-[3-(3,5-difluorophenyl)-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   82)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[4-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide;-   83)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[[4-(trifluoromethyl)phenyl]methyl]-1-piperidyl]pyridine-3-carboxamide;-   84)    N-(2-sulfamoyl-4-pyridyl)-2-thiomorpholino-5-(trifluoromethyl)pyridine-3-carboxamide;-   85)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyridine-3-carboxamide;-   86)    2-(3-benzyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   87)    2-[3,3-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   88)    2-(2,2-dimethylmorpholin-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   89)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[8-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]pyridine-3-carboxamide;-   90)    N-(2-sulfamoyl-4-pyridyl)-2-[4-(trifluoromethoxy)isoindolin-2-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;-   91)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[2-[4-(trifluoromethyl)phenyl]morpholin-4-yl]pyridine-3-carboxamide;-   92)    N-(2-sulfamoyl-4-pyridyl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   93)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)azetidin-1-yl]pyridine-3-carboxamide;-   94)    2-(3-pyrazol-1-ylpyrrolidin-1-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   95)    2-[2-(4-fluorophenyl)-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   96)    2-(2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrol-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;-   97)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[4-(trifluoromethyl)phenoxy]azetidin-1-yl]pyridine-3-carboxamide;-   98)    N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[4-[3-(trifluoromethyl)phenoxy]-1-piperidyl]pyridine-3-carboxamide;-   99)    2-[4-(cyclopropylmethyl)-3-oxo-piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;-   100)    N-(2-sulfamoyl-4-pyridyl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;-   101)    5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;-   102)    2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   103)    2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   104)    (S)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;-   105)    (R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;-   106)    2-[(2R)-6,6-dimethyl-2-(trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   107)    2-(2,2-dimethyl-1,4-oxazepan-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   108)    2-[(7S)-7-methyl-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   109)    N-[2-(tert-butylsulfamoyl)-4-pyridyl]-5-chloro-2-(4,4-difluoroazepan-1-yl)pyridine-3-carboxamide;-   110)    2-[(2S)-2-methylmorpholin-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   111)    2-[(2R)-2-methyl-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   112)    2-(3-hydroxy-3-methyl-1-piperidyl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   113)    2-(6-fluoro-1,1-dimethyl-isoindolin-2-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   114)    2-(azepan-1-yl)-N-(2-methyl-5-sulfamoylthiophen-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   115)    2-(4,4-difluoro-5-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;-   116)    5-chloro-2-[(7R)-7-(difluoromethyl)-1,4-oxazepan-4-yl]-6-methyl-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;-   117)    5-chloro-2-[(7S)-7-(difluoromethyl)-1,4-oxazepan-4-yl]-6-methyl-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;-   118)    (R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;-   119)    (S)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;-   120)    2-[(2S,7R)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   121)    2-((2R,7S)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   122)    2-((2R,7R)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   123)    2-((2S,7S)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   124)    (S)-5-chloro-2-(2-(difluoromethyl)morpholino)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;-   125)    (R)-5-chloro-2-(2-(difluoromethyl)morpholino)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;-   126)    N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide;-   127)    (R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)nicotinamide;-   128)    N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide;-   129)    (S)-2-(3-cyanopyrrolidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   130)    (R)-2-(3-cyanopyrrolidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl-)nicotinamide;-   131)    2-(4,4-difluoro-3-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   132)    2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;-   133)    2-((2R,6S)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   134)    2-((2S,6R)-2-ethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   135)    (R)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   136)    (S)-2-(2,2-dimethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   137)    4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;-   138)    6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;-   139)    2-(azepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   140)    2-(azepan-1-yl)-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   141)    2-(azepan-1-yl)-N-(6-sulfamoyl-2-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   142)    2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   143)    N-(2-methoxypyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamide;-   144)    2-(4,4-difluoroazepan-1-yl)-N-(5-sulfamoyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   145)    2-(azepan-1-yl)-N-(5-sulfamoyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   146)    2-(4,4-difluoroazepan-1-yl)-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   147)    2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide;-   148)    2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoro-methyl)-pyridine-3-carboxamide;-   149) 2-[(3    S)-4,4-difluoro-3-methyl-1-piperidyl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoro-methyl)-pyridine-3-carboxamide;-   150)    N-(2-cyano-4-pyridyl)-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-5-(trifluoro-methyl)-pyridine-3-carboxamide;-   151)    N-(2-methylsulfonyl-4-pyridyl)-2-[(1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;-   152)    2-[(1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   153) 2-[(1R,5S)-3-azabicyclo[3.2.    O]heptan-3-yl]-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   154)    (R)—N-(2-cyanopyridin-4-yl)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-S-(trifluoromethyl)-nicotinamide;-   155)    (S)—N-(2-cyanopyridin-4-yl)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-S-(trifluoromethyl)-nicotinamide;-   156)    4-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-S-(trifluoromethyl)nicotinamido)-picolinamide;-   157) N-(2-carbamoyl-4-pyridyl)-2-[(3    S)-4,4-difluoro-3-methyl-1-piperidyl]-5-(trifluoromethyl)-pyridine-3-carboxamide;-   158)    N-(2-carbamoyl-4-pyridyl)-2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-5-(trifluoromethyl)-pyridine-3-carboxamide;-   159)    2-(4,4-difluoropiperidin-1l-yl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   160)    5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   161)    5-chloro-6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   162)    (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)nicotinamide;-   163)    (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)nicotinamide;-   164)    (S)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;-   165)    (R)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;-   166)    6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1l-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   167)    6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   168)    6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   169)    5-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoyl-pyridin-4-yl)nicotinamide;-   170)    6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   171)    2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   172)    5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   173)    4-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-sulfamoylpyridin-4-yl)pyrimidine-5-carboxamide;-   174)    2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   175)    2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)    nicotinamide;-   176)    4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonic    acid;-   177)    2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethoxy)nicotinamide-   178)    2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   179)    3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;-   180)    5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;-   181)    5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)-nicotinamide;-   182)    5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methoxy)-nicotinamide;-   183)    2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(2,2,2-trifluoro-ethoxy)-nicotinamide;-   184)    2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   185)    6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;-   186)    2-(azepan-1-yl)-N-(5-fluoropyridin-3-yl)-5-(trifluoromethyl)nicotinamide;-   187)    2-(azepan-1-yl)-5-chloro-N-(2-methoxy-4-pyridyl)-4,6-dimethyl-pyridine-3-carboxamide;-   188)    2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   189)    5-chloro-2-(4,4-difluoro-1-piperidyl)-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   190)    2-(6-azaspiro[2.5]octan-6-yl)-5-chloro-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   191)    5-chloro-4,6-dimethyl-2-(1-piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   192)    2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;-   193)    2-(azepan-1-yl)-N-(5-cyano-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   194)    2-(azepan-1-yl)-N-(5-methoxy-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   195)    2-(azepan-1-yl)-N-(5-methyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   196)    2-(azepan-1-yl)-N-[5-(hydroxymethyl)-3-pyridyl]-5-(trifluoromethyl)pyridine-3-carboxamide;-   197)    2-(azepan-1-yl)-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   198)    2-(azepan-1-yl)-N-(2-ethylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   199)    2-(azepan-1-yl)-N-(3-bromoimidazo[1,2-a]pyridin-6-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;-   200)    2-(azepan-1-yl)-5-(trifluoromethyl)-N-[5-(trifluoromethyl)-3-pyridyl]pyridine-3-carboxamide;-   201)    2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   202)    5-chloro-4,6-dimethyl-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   203)    4-(2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;-   204)    5-bromo-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   205)    2-(4,4-difluoropiperidin-1-yl)-5-phenyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   206)    2-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   207)    2-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;-   208)    N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)-nicotinamide;-   209)    5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide;-   210)    2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;-   211)    5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(piperidin-1-yl)nicotinamide;-   212)    2-(azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)nicotinamide;    and-   213)    2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide;-   214)    5-chloro-2-(4,4-difluorocyclohexyl)-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   215)    5-chloro-2-cycloheptyl-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide-   216)    5-chloro-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrazine-2-carboxamide;-   217)    5-chloro-4,6-dimethyl-2-(4-methylcyclohexyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;-   and-   218)    5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;    or a pharmaceutically acceptable salt thereof.

Although the specific stereochemistries described above are preferred,other stereoisomers, including diastereoisomers, enantiomers, epimers,and mixtures of these may also have utility in treating Na_(v)1.8mediated diseases.

Synthetic methods for making the compounds are disclosed in the Examplesshown below. Where synthetic details are not provided in the examples,the compounds are readily made by a person of ordinary skill in the artof medicinal chemistry or synthetic organic chemistry by applying thesynthetic information provided herein. Where a stereochemical center isnot defined, the structure represents a mixture of stereoisomers at thatcenter. For such compounds, the individual stereoisomers, includingenantiomers, diastereoisomers, and mixtures of these are also compoundsof the invention.

Definitions

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a saturated monocyclic, bicyclic, spirocyclic orbridged carbocyclic ring, having a specified number of carbon atoms.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like. In one embodiment of the presentinvention, cycloalkyl is selected from: cyclopropane, cyclobutane andcyclohexane. In another embodiment, cycloalkyl is cyclopropane,cyclobutane or cyclopentane. In another embodiment, cycloalkyl iscyclopropane or cyclobutane. In another embodiment, cycloalkyl iscyclopropane. In another embodiment, cycloalkyl is cyclobutane. Inanother embodiment, cycloalkyl is cyclopentane. In another embodiment,cycloalkyl is cyclohexane. In another embodiment, cycloalkyl iscycloheptane.

“Cycloheteroalkyl” means a saturated or partly unsaturated non-aromaticmonocyclic, bicyclic, spirocyclic or bridged ring or ring system havinga specified number of carbon atoms and containing at least one ringheteroatom selected from N, NH, S (including SO and SO₂) and O. Thecycloheteroalkyl ring may be substituted on the ring carbons and/or thering nitrogen or sulfur. Examples of cycloheteroalkyl includetetrahydrofuran, pyrrolidine, tetrahydrothiophene, azetidine,piperazine, piperidine, morpholine, oxetane and tetrahydropyran. In oneembodiment of the present invention, cycloheteroalkyl is selected from:pyrrolidine, azetidine, piperidine, piperazine, azepane, azocane,morpholine, thiomorpholine, thiomorpholine dione, oxazepane,1,4-thiazepane, isoindoline, dihydroisoquinoline,tetra-hydroisoquinoline, octahydro-isoindole, azabicyclo[2.2.1]heptane,oxa-azabicyclo[2.2.1]-heptane, azabicyclo[3.1.1]heptane,azabicyclo[4.1.0]heptane, azabicyclo[3.2.1]octane,diazabicyclo[3.2.1]octane, oxa-azabicyclo-[3.2.1]octane,azabicyclo[3.2.0]heptane, oxa-azabicyclo[3.2.0]heptane,azaspiro[2.5]octane, azaspiro[2.6]nonane, azaspiro[3.5]nonane,oxa-azaspiro[3.5]nonane, oxa-azaspiro[4.5]decane,dihydrothieno[3,2-c]pyridine, dihydro-thiazolo[4,5-c]pyridine,dihydrooxazolo[4,5-c]pyridine, dihydroimidazo[1,2-a]pyrazine,hexahydrofuro[3,2-b]pyrrole, hexahydrocyclopenta[c]pyrrole,octahydrocyclpenta[c]pyrrole, and azatricyclo[4.3.1.13,8]undecane. Inanother embodiment, cycloheteroalkyl is selected from: pyrrolidine,azetidine, piperidine, piperazine, azepane, morpholine, thiomorpholine,oxazepane, isoindoline, dihydroisoquinoline, azabicyclo[2.2.1]heptane,azabicyclo[3.1.1]-heptane, azabicyclo[4.1.0]heptane,azabicyclo[3.2.1]octane, azabicyclo[3.2.0]heptane, azaspiro[2.5]octane,dihydrothieno[3,2-c]pyridine, dihydroimidazo[1,2-a]pyrazine, andhexahydrofuro[3,2-b]pyrrole. In another embodiment, cycloheteroalkyl isselected from: azepane, morpholine and piperidine. In anotherembodiment, cycloheteroalkyl is azepane. In another embodiment,cycloheteroalkyl is morpholine. In another embodiment, cycloheteroalkylis piperidine.

“Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromaticring or ring system containing 6-14 carbon atoms, wherein at least oneof the rings is aromatic. Examples of aryl include phenyl and naphthyl.In one embodiment of the present invention, aryl is phenyl.

“Heteroaryl” means a monocyclic, bicyclic or tricyclic ring or ringsystem containing 5-14 ring atoms and containing at least one ringheteroatom selected from N, NH, S (including SO and SO₂) and O, whereinat least one of the heteroatom containing rings is aromatic. Examples ofheteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl,pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl,isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. In oneembodiment of the present invention, heteroaryl is a 5 or 6 memberedheteroaryl ring. In another embodiment, heteroaryl is selected from:pyrazole, pyridyl, isoxazole and thiazole. In another embodiment of thepresent invention, heteroaryl is selected from: pyridine, pyrimidine,pyrazine, pyridazine, indazole, imidazo[1,2-a]pyridine,1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,pyrrolo[3,2-c]pyridine, pyrrolo[2,3-b]pyridine, benzimidazole,imidazole, pyrazole, thiophene, furan, 1,2,4-oxadiazole,1,3,4-oxadiazole, oxazole, isoxazole, isothiazole, thiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole; 4H-pyrido[2,3-e][1,2,4]thiadiazine1,1-dioxide, 2H-pyrido[2,3-e][1,2]thiazine 1,1-dioxide,2,3-dihydroisothiazolo[4,5-b]pyridine 1,1-dioxide, and3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazine 1,1-dioxide. In anotherembodiment of the present invention, heteroaryl is selected from:pyridine, pyrimidine, and pyridazine. In another embodiment of thepresent invention, heteroaryl is pyridine.

“Halogen” includes fluorine, chlorine, bromine and iodine. In oneembodiment, halogen is fluorine, chorine or bromine. In anotherembodiment, halogen is fluorine or chlorine. In another embodiment,halogen is fluorine or bromine. In another embodiment, halogen isfluorine. In another embodiment, halogen is chlorine. In anotherembodiment, halogen is bromine.

“Me” represents methyl.

“Oxo” represents ═O.

“Saturated” means containing only single bonds.

“Unsaturated” means containing at least one double or triple bond. Inone embodiment, unsaturated means containing at least one double bond.In another embodiment, unsaturated means containing at least one triplebond.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A squiggly line across abond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, salts and/or dosage formswhich are, using sound medical judgment, and following all applicablegovernment regulations, safe and suitable for administration to a humanbeing or an animal.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to encompass all such isomeric forms of the compoundsof Formula I.

The independent syntheses of optical isomers and diastereoisomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration or sufficient heavy atoms to makean absolute assignment.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well-known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I. Forexample, the compounds of formula I include the following tautomers:

In the compounds of general formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H), deuterium (²H), and tritium (³H). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Tritium is radioactive and may therefore provide for aradiolabeled compound, useful as a tracer in metabolic or kineticstudies. Isotopically-enriched compounds within structural formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Salts

It will be understood that, as used herein, references to the compoundsof the present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

The term “prodrug” means compounds that are rapidly transformed, forexample, by hydrolysis in blood, in vivo to the parent compound, e.g.,conversion of a prodrug of Formula A to a compound of Formula A, or to asalt thereof; a thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference. The scope ofthis invention includes prodrugs of the novel compounds of thisinvention.

Solvates, and in particular, the hydrates of the compounds of thepresent invention are included in the present invention as well.

Utilities

The compound of the present invention are selective inhibitors ofNa_(v)1.8 sodium ion channel activity or have selective activity asNa_(v)1.8 sodium ion channel blockers. In one embodiment, the compoundsof the present invention exhibit at least 10-fold selectivity forNa_(v)1.8 sodium channels over Na_(v)1.5 sodium channels, and in someembodiments exhibit at least 100-fold selectivity for Na_(v)1.8 sodiumchannels over Na_(v)1.5 sodium channels based on functional potency(IC₅₀ values) for each channel in Qube® assay system.

The compounds of the present invention are potent inhibitors ofNa_(v)1.8 channel activity. The compounds, and pharmaceuticallyacceptable salts thereof, may be efficacious in the treatment ofdiseases, disorders and conditions that are mediated by the inhibitionof Na_(v)1.8 sodium ion channel activity and/or Na_(v)1.8 receptors.

Diseases, disorders or conditions mediated by Na_(v)1.8 sodium ionchannel activity and/or Na_(v)1.8 receptors, include but are not limitedto nociception, osteoarthritis, peripheral neuropathy, inheritederythromelalgia, multiple sclerosis, asthma, pruritus, acute itch,chronic itch, migraine, neurodegeneration following ischemia, epilepsy,inflammatory pain, spontaneous pain, acute pain, peri-operative pain,post-operative pain, neuropathic pain, postherpetic neuralgia,trigeminal neuralgia, diabetic neuropathy, chronic lower back pain,phantom limb pain, pain resulting from cancer and chemotherapy, chronicpelvic pain, pain syndromes, and complex regional pain syndromes.

One or more of these conditions or diseases may be treated, managed,prevented, reduced, alleviated, ameliorated or controlled by theadministration of a therapeutically effective amount of a compound ofthe present invention, or a pharmaceutically acceptable salt thereof, toa patient in need of treatment. Also, the compounds of the presentinvention may be used for the manufacture of a medicament which may beuseful for treating, preventing, managing, alleviating, ameliorating orcontrolling one or more of these conditions, diseases or disorders:nociception, osteoarthritis, peripheral neuropathy, inheritederythromelalgia, multiple sclerosis, asthma, pruritus, acute itch,chronic itch, migraine, neurodegeneration following ischemia, epilepsy,inflammatory pain, spontaneous pain, acute pain, peri-operative pain,post-operative pain, neuropathic pain, postherpetic neuralgia,trigeminal neuralgia, diabetic neuropathy, chronic lower back pain,phantom limb pain, pain resulting from cancer and chemotherapy, chronicpelvic pain, pain syndromes, and complex regional pain syndromes.

Preferred uses of the compounds may be for the treatment of one or moreof the following diseases by administering a therapeutically effectiveamount to a patient in need of treatment. The compounds may be used formanufacturing a medicament for the treatment of one or more of thesediseases:

1) pain conditions,

2) pruritic conditions, and

3) cough conditions.

In one embodiment of the present invention, the pain condition is anacute pain or chronic pain disorder. In another embodiment of thepresent invention, the the pain condition is an acute pain disorder.

The compounds of the present invention may be effective in treatingnociception. Nociception or pain is essential for survival and oftenserves a protective function. However, the pain associated with surgicalprocedures and current therapies to relieve that pain, can delayrecovery after surgery and increase the length of hospital stays. Asmany as 80% of surgical patients experience post-operative pain due totissue damage, and damage to peripheral nerves and subsequentinflammation. Approximately 10-50% of surgical patients will developchronic pain after surgery often because the nerve damage results inlasting neuropathic pain once the wound has healed.

The compounds of the present invention may be effective in treatingosteoarthritis. Osteoarthritis is type of arthritis caused byinflammation, breakdown, and eventual loss of cartilage in the joints.The standards of care for pain associated with osteoarthritis arenon-steroidal anti-inflammatory drugs (NSAIDs), for example celecoxiband diclofenac (reviewed in Zeng et al., 2018). Patients that do notrespond to NSAID therapies are typically treated with low dose opiates,such as hydrocodone. Patients that are refractory to the above therapieswill usually opt for total joint replacement.

The compounds of the present invention may be effective in treatingperipheral neuropathy. Peripheral neuropathy is nerve damage caused bychronically high blood sugar and diabetes. It leads to numbness, loss ofsensation, and sometimes pain in distal limbs such as feet, legs, orhands. It is the most common complication of diabetes. The standards ofcare for the treatment of painful diabetic neuropathy aregabapentinoids, for example gabapentin and pregabalin. Some patientswill respond well to tricyclic antidepressants such as amitriptyline,while other patients get significant relief using SRI/NRI drugs such asduloxetine (Schreiber et al., World J Diabetes. 2015 Apr. 15;6(3):432-44). Many options are available, however side-effects arecommon (e.g. dizziness, nausea) which limit their full potential.

The compounds of the present invention may be effective in treatinginherited erythromelalgia. Inherited erythromelalgia (IEM) is a chronicpain syndrome which has been linked to mutations in severalvoltage-gated sodium channels, including Nav1.8 (Kist et al., PLoS One.2016 Sep. 6; 11(9):e0161789). Patients present with the classic “glovesand stocking” flare pattern on distal regions such as hands and feet,typically brought on with warm temperatures and exercise. Some patientsfind relief from the burning pain associated with flares by cold waterimmersion. Although medications that affect voltage-gated sodiumchannels (eg, lidocaine and mexiletine) show promise, there is nocurrent standard of care to treat IEM.

The compounds of the present invention may be effective in treatingneuropathic pain. Neuropathic pain is pain caused by damage or diseaseaffecting the somatosensory nervous system. It has been demonstrated inhuman patients, as well as in animal models of neuropathic pain, thatdamage to primary afferent sensory neurons can lead to neuroma formationand spontaneous activity, as well as evoked activity in response tonormally innocuous stimuli. (Colloca et al., Nat Rev Dis Primers. 2017Feb. 16; 3:17002; Coward et al., Pain. 2000 March; 85(1-2):41-50;Yiangou et al., FEBS Lett. 2000 Feb. 11; 467(2-3):249-52; Carter et al.,Phys Med Rehabil Clin N Am. 2001 May; 12(2):447-59). Some nerve injuriesresult in an increase in Navy 1.8 expression, which is believed to be anunderlying mechanism for pathological pain. (Black et al., Ann Neurol.2008 December; 64(6):644-53; Bird et al., Br J Pharmacol. 2015 May;172(10):2654-70). Injuries of the peripheral nervous system often resultin neuropathic pain persisting long after an initial injury resolves.Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chroniclower back pain, lumbar radiculopathy, phantom limb pain, pain resultingfrom cancer and chemotherapy, chronic pelvic pain, complex regional painsyndrome and related neuralgias, and painful conditions that arise dueto gain-of-function mutations in Nav1.8 (Huang et al., J Neurosci. 2013Aug. 28; 33(35):14087-97; Kist et al., PLoS One. 2016 Sep. 6;11(9):e0161789; Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81;and Schreiber et al., World J Diabetes. 2015 Apr. 15; 6(3):432-44.

The ectopic activity of normally silent sensory neurons is thought tocontribute to the generation and maintenance of neuropathic pain, whichis generally assumed to be associated with an increase in sodium channelactivity in the injured nerve. (Wood et al., Curr Opin Pharmacol. 2001February; 1(1): 17-21; Baker et al., TRENDS in Pharmacological Sciences,2001, 22(1): 27-31). Standards of care for neuropathic pain varyconsiderably depending on the particular condition, but first linetherapies are typically pregabalin, gabapentin, tricyclicantidepressants (e.g. amitriptyline), and SRI/NRI drugs (e.g.duloxetine). Patients refractory to these therapies are usuallyprescribed low dose opiates (e.g. hydrocodone).

The compounds of the present invention may be effective in treatingmultiple sclerosis. Recent evidence points to a potential role forNav1.8 in multiple sclerosis. Nav1.8 expression in cerebellum has beenidentified in tissues taken from animal models of multiple sclerosis(EAE model) and in postmortem brains from patients suffering frommultiple sclerosis (MS) (Shields et al., Ann Neurol. 2012 February;71(2):186-94; Black et al., Proc Natl Acad Sci USA. 2000 Oct. 10;97(21):11598-602). Also, two SCN10A polymorphisms showed significantassociation with MS (Roostaei et al., Neurology. 2016 Feb. 2; 86(5):410-7). When Nav1.8 is overexpressed in cerebellum, mice developataxic-related motor deficits which are ameliorated with oral deliveryof a selective small molecule Nav1.8 antagonist (Shields et al., PLoSOne. 2015 Mar. 6; 10(3)). These studies suggest that a Nav1.8 antagonistmay be a useful therapy to treat symptoms related to multiple sclerosis.

The compounds of the present invention may be effective in treatingasthma. Asthma is caused by airway inflammation in which a person'sairways become hyper-responsive, narrow and swollen, which makes itdifficult to breathe. These symptoms are typically triggered through anallergic reaction (Nair P et al., J Allergy Clin Immunol Pract. 2017May-June; 5(3):649-659). In a preclinical model of asthma, deletion ofNav1.8-containing neurons, or inhibition of nerve fibers via smallmolecules reduces airway inflammation and immune cell infiltration(Talbot et al., Neuron. 2015 Jul. 15; 87(2):341-54). Selective Nav1.8antagonists may be a useful therapy to prevent airway hypersensitivitycaused by immune cell infiltration.

The compounds of the present invention may be effective in treatingpruritus. Pruritus, also commonly known as itch, affects approximately4% of the global population is an unpleasant sensation that elicits thedesire or reflex to scratch, and is regarded as closely related to pain(Luo et al., Cell Mol Life Sci. 2015 September; 72 (17): 3201-23).Theories on the origin of itch implicate the subtle, low-frequencyactivation of nociceptors (pain-sensing neurons); however, it has beendescribed that some afferents preferentially respond to histamine, whichinduces itch (Schmelz et al., J Neurosci. 1997 Oct. 15; 17(20):8003-8).At the same time, it has been found that histamine-responding neuronsalso respond to capsaicin which produces pain (McMahon et al., Trends inNeuroscience 1992, 15:497-501). Members of the transient receptorpotential (TRP) family, and nerve growth factor (NGF) are both known toplay a role in itch and pain, and clinically, both maladies are treatedwith therapeutic agents such as gabapentin and antidepressants.Therefore, it continues to be accepted that the underlying mechanisms ofpain and itch are highly interwoven and complex, and distinguishingpan-selective or itch-selective pathways remains ambiguous (Ikoma etal., Nat Rev Neurosci. 2006 July; 7(7):535-47). A role for Nav1.8 inpruritis was studied using a mouse transgenically expressing aconstitutively active form of the serine/threonine kinase BRAF wasexpressed in Navy 1.8-expressing neurons. This resulted in enhancedpruriceptor excitability, and heightened evoked and spontaneousscratching behavior (Zhao et al., 2013). In skin, pruritogens arereleased from keratinocytes, lymphocytes, mast cells, and eosinophilsduring inflammation. These molecules act directly on free nerve endingswhich express Nav1.8 to induce itch (Riol-Blanco et al., Nature. 2014Jun. 5; 510 (7503): 157-61). Chronic and acute itch can arise from manydifferent insults, diseases and disorders, and may be classified asdermal or pruriceptive, neurogenic, neuropathic, or psychogenic: itchcan arise from both systemic disorders, skin disorders, as well asphysical or chemical insult to the dermis. Pathologically, conditionssuch as dry skin, eczema, psoriasis, varicella zoster, urticaria,scabies, renal failure, cirrhosis, lymphoma, iron deficiency, diabetes,menopause, polycythemia, uremia, and hyperthyroidism can cause itch, ascan diseases of the nervous system such as tumors, multiple sclerosis,peripheral neuropathy, nerve compression, and delusions related toobsessive-compulsive disorders. Medicines such as opioids andchloroquine can also trigger itch (Ikoma et al., Nat Rev Neurosci. 2006July; 7(7):535-47). Itching following burn is also an extremely seriousclinical problem as it hampers the healing process, resulting inpermanent scaring, and negatively impacting quality of life (Van Loey etal., Br J Dermatol. 2008 January; 158(1):95-100).

The invention also includes pharmaceutically acceptable salts of thecompounds, and pharmaceutical compositions comprising the compounds anda pharmaceutically acceptable carrier.

The compounds, or pharmaceutically acceptable salts thereof, may beuseful in treating pain conditions, pruritic conditions, and coughconditions.

A compound of the present invention, or a pharmaceutically acceptablesalt thereof, may be used in the manufacture of a medicament for thetreatment of pain conditions, pruritic conditions, and cough conditionsin a human or other mammalian patient.

A method of treating a pain conditions comprises the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound, to a patient in need of treatment.A method of treating a pruritic condition comprises the administrationof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising the compound, to a patient in needof treatment. A method of treating a cough condition comprises theadministration of a therapeutically effective amount of a compound ofthe present invention, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition comprising the compound, to a patient inneed of treatment. Other medical uses of the compounds of the presentinvention are described herein.

The term “pain condition” as used herein includes, but are not limitedto, acute pain, peri-operative pain, pre-operative pain, post-operativepain, neuropathic pain, post herpetic neuralgia, trigeminal neuralgia,diabetic neuropathy, chronic lower back pain, phantom limb pain, chronicpelvic pain, vulvodynia, complex regional pain syndrome and relatedneuralgias, pain associated with cancer and chemotherapy, painassociated with HIV, and HIV treatment-induced neuropathy, nerve injury,root avulsions, painful traumatic mononeuropathy, painfulpolyneuropathy, erythromyelalgia, paroxysmal extreme pain disorder,small fiber neuropathy, burning mouth syndrome, central pain syndromes(potentially caused by virtually any lesion at any level of the nervoussystem), postsurgical pain syndromes (e.g., post mastectomy syndrome,post thoracotomy syndrome, stump pain)), bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, myofascial pain(muscular injury, fibromyalgia), perioperative pain (general surgery,gynecological), chronic pain, dysmennorhea, pain associated with angina,inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), shouldertendonitis or bursitis, gouty arthritis, and aolymyalgia rheumatica,primary hyperalgesia, secondary hyperalgesia, primary allodynia,secondary allodynia, or other pain caused by central sensitization,complex regional pain syndrome, chronic arthritic pain and relatedneuralgias acute pain, migraine, migraine headache, headache pain,cluster headache, non-vascular headache, traumatic nerve injury, nervecompression or entrapment, and neuroma pain,

The term “pruritic condition” or “pruritic disorder” as used hereinincludes, but is not limited to, conditions with an unpleasant sensationthat provokes the desire to scratch, such as chronic itch.

The term “cough condition” or “cough disorder” as used herein includes,but is not limited to, chronic cough, neuropathic cough or cough due toneurological conditions.

Treatment of a disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors refers to theadministration of the compounds of the present invention to a subjectwith the disease, disorder or condition. One outcome of treatment may bereducing the disease, disorder or condition mediated by Na_(v)1.8 sodiumion channel activity or Nav1.8 receptors. Another outcome of treatmentmay be alleviating the disease, disorder or condition mediated byNa_(v)1.8 sodium ion channel activity or Na_(v)1.8 receptors. Anotheroutcome of treatment may be ameliorating the disease, disorder orcondition mediated by Na_(v)1.8 sodium ion channel activity or Na_(v)1.8receptors. Another outcome of treatment may be suppressing the disease,disorder or condition mediated by Na_(v)1.8 sodium ion channel activityor Na_(v)1.8 receptors. Another outcome of treatment may be managing thedisease, disorder or condition mediated by Na_(v)1.8 sodium ion channelactivity or Na_(v)1.8 receptors.

Another outcome of treatment may be preventing the disease, disorder orcondition mediated by Na_(v)1.8 sodium ion channel activity or Na_(v)1.8receptors.

Prevention of the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors refers to theadministration of the compounds of the present invention to a subject atrisk of the disease, disorder or condition. One outcome of preventionmay be reducing the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe suppressing the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe ameliorating the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe alleviating the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe managing the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition.

One outcome of treatment may be reducing the amount of pain experiencedby a subject relative to that subject's pain immediately before theadministration of the compounds of the present invention. Anotheroutcome of treatment may be alleviating the amount of pain experiencedby a subject relative to that subject's pain immediately before theadministration of the compounds of the present invention. Anotheroutcome of treatment may be ameliorating the amount of pain experiencedby a subject relative to that subject's pain immediately before theadministration of the compounds of the present invention. Anotheroutcome of treatment may be suppressing the amount of pain experiencedby a subject relative to that subject's pain immediately before theadministration of the compounds of the present invention. Anotheroutcome of treatment may be managing the amount of pain experienced by asubject relative to that subject's pain immediately before theadministration of the compounds of the present invention. Anotheroutcome of treatment may be ameliorating the amount of pain experiencedby a subject relative to that subject's pain immediately before theadministration of the compounds of the present invention.

Another outcome of treatment may be preventing further pain experiencedby a subject after the administration of the compounds of the presentinvention.

Prevention of pain refers to the administration of the compounds of thepresent invention to reduce the pain of a subject at risk of pain.Prevention includes, but is not limited to, the administration to asubject prior to surgery or other expected painful event. One outcome ofprevention may be reducing pain in a subject at risk of pain. Anotheroutcome of prevention may be suppressing pain in a subject at risk ofpain. Another outcome of prevention may be ameliorating pain in asubject at risk of pain. Another outcome of prevention may bealleviating pain in a subject at risk of pain. Another outcome ofprevention may be managing pain in a subject at risk of pain.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual or mammal in need oftreatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to themammal in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician or veterinarian in charge of the case, butdepends on factors such as the exact disease to be treated, the severityof the disease and other diseases or conditions from which the patientsuffers, the chosen route of administration other drugs and treatmentswhich the patient may concomitantly require, and other factors in thephysician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, intravenous, infusion,subcutaneous, transcutaneous, intramuscular, intradermal, transmucosal,intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal, andthe like may be employed. Dosage forms include tablets, troches,dispersions, suspensions, solutions, capsules, creams, ointments,aerosols, and the like. Preferably compounds of the present inventionare administered orally.

In the treatment or prevention of disorders, diseases and/or conditionswhich require inhibition of Na_(v)1.8 sodium ion channel activity, asuitable dosage level will generally be about 0.0001 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. In one embodiment, a suitable dosage level may be about0.001 to 500 mg per kg patient body weight per day. In anotherembodiment, a suitable dosage level may be about 0.001 to about 250mg/kg per day. In another embodiment, a suitable dosage level may beabout 0.01 to about 250 mg/kg per day. In another embodiment, a suitabledosage level may be about 0.1 to about 100 mg/kg per day. In anotherembodiment, a suitable dosage level may be about 0.05 to 100 mg/kg perday. In another embodiment, a suitable dosage level may be about 0.1 to50 mg/kg per day. In another embodiment, a suitable dosage level may beabout 0.05 to 0.5 mg/kg per day. In another embodiment, a suitabledosage level may be about 0.5 to 5 mg/kg per day. In another embodiment,a suitable dosage level may be about 5 to 50 mg/kg per day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 mg of the active ingredient,particularly 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 2.5,5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The compounds may be administered on aregimen of 1 to 8 times per day; preferably, 1 to 4 times a day; morepreferably once or twice per day. This dosage regimen may be adjusted toprovide the optimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of this invention may be used in pharmaceuticalcompositions comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds of this invention may be used in pharmaceuticalcompositions that include one or more other active pharmaceuticalingredients. The compounds of this invention may also be used inpharmaceutical compositions in which the compound of the presentinvention or a pharmaceutically acceptable salt thereof is the onlyactive ingredient.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Compounds of the present invention may be used in combination with otherdrugs that may also be useful in the treatment or amelioration of thediseases or conditions for which compounds of the present invention areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound of the present invention. In the treatment of patients who havepain conditions, pruritic conditions and cough conditions, more than onedrug is commonly administered. The compounds of this invention maygenerally be administered to a patient who is already taking one or moreother drugs for these conditions. Often the compounds will beadministered to a patient who is already being treated with one or moreanti-pain compounds when the patient's pain is not adequately respondingto treatment.

The combination therapy also includes therapies in which the compound ofthe present invention and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof the present invention.

Examples of other active ingredients that may be administered incombination with a compound of the present invention, and eitheradministered separately or in the same pharmaceutical composition,include but are not limited to:

(i) an opioid agonist;

(ii) an opioid antagonist;

(iii) a calcium channel antagonist;

(iv) a NMDA receptor agonist;

(v) a NMDA receptor antagonist;

(vi) a COX-2 selective inhibitor;

(vii) a NSAID (non-steroidal anti-inflammatory drug); and

(viii) an analgesic;

(ix) a sodium channel inhibitor;

(x) an anti-NGF antibody;

(xi) a Na_(v)1.7 inhibitor;

(xii) a HCN inhibitor;

(xiii) a TRPV 1 antagonist;

(xiv) a Na_(v)1.7 biological; and

(xv) a Na_(v)1.8 biological; and

pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, the pharmaceuticalcomposition comprises:

(1) a compound of Claim 1 or a pharmaceutically acceptable salt thereof;

(2) one or more compounds, or pharmaceutically acceptable salts thereof,selected from the group consisting of:

(i) an opioid agonist;

(ii) an opioid antagonist;

(iii) a calcium channel antagonist;

(iv) a NMDA receptor agonist;

(v) a NMDA receptor antagonist;

(vi) a COX-2 selective inhibitor;

(vii) a NSAID (non-steroidal anti-inflammatory drug); and

(viii) an analgesic;

(ix) a sodium channel inhibitor;

(x) an anti-NGF antibody;

(xi) a Na_(v)1.7 inhibitor;

(xii) a HCN inhibitor;

(xiii) a TRPV 1 antagonist;

(xiv) a Na_(v)1.7 biological; and

(xv) a Na_(v)1.8 biological; and

pharmaceutically acceptable salts thereof; and

(3) a pharmaceutically acceptable carrier.

A Nav 1.7 biological means a protein, including, but not limited to,antibodies, nanobodies and peptides, that inhibits the function of theNav1.7 channel. A Nav 1.8 biological means a protein, including, but notlimited to, antibodies, nanobodies and peptides, that inhibits thefunction of the Navy 1.8 channel.

Specific compounds of use in combination with a compound of the presentinvention include: sodium channel inhibitors, including but not limitedto, lidocaine including the lidocaine patch; tricyclic antidepressantsincluding, but not limited to, amitriptyline; and SRI/NRI drugs,including but not limited to, duloxetine.

Suitable opioid agonists include, but are not limited to, codeine,fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine,methadone, morphine, oxycodone, oxymorphone, buprenorphine, butorphanol,dezocine, nalbuphine, pentazocine, and tramadol.

Suitable opioid antagonists include, but are not limited to, naltrexoneand naloxone.

Suitable calcium channel antagonists include, but are not limited to,Amlodipine, Diltiazem, Felodipine, gabapentin, Isradipine, Nicardipine,Nifedipine, Nisoldipine, pregabalin, Verapamil, and ziconitide.

Suitable NMDA receptor antagonists include, but are not limited to,ketamine, methadone, memantine, amantadine, and dextromethorphan.

Suitable COX-2 inhibitors include, but are not limited to, celecoxib,etoricoxib and parecoxib.

Suitable NSAIDs or non-steroidal anti-inflammatory drugs include, butare not limited to, aspirin, diclofenac, diflunisal, etodolac,fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen,meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium,oxaprozin, piroxicam, sulindac, and tolmetin.

Suitable analgesics include, but are not limited to, acetaminophen andduloxetine.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds with two or more active compounds selected from: opioidagonists; opioid antagonists; calcium channel antagonists; NMDA receptoragonists; NMDA receptor antagonists; COX-2 selective inhibitors; NSAIDs(non-steroidal anti-inflammatory drugs); and an analgesic.

The compounds of the present invention, or a pharmaceutically acceptablesalt thereof, may also be used in combination with spinal cordstimulation therapy and cutaneous stimulation therapy.

The present invention also provides a method for the treatment orprevention of a Na_(v)1.8 sodium ion channel activity mediated disease,disorder or condition, which method comprises administration to apatient in need of such treatment or at risk of developing a Na_(v)1.8sodium ion channel activity mediated disease with a therapeuticallyeffective amount of a Na_(v)1.8 sodium ion channel activity inhibitorand an amount of one or more active ingredients, such that together theygive effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a Na_(v)1.8 sodium ion channelactivity inhibitor and one or more active ingredients, together with atleast one pharmaceutically acceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a Na_(v)1.8 sodium ion channel activity inhibitorand one or more active ingredients for the manufacture of a medicamentfor the treatment or prevention of a Na_(v)1.8 sodium ion channelactivity mediated disease, disorder or condition. In a further oralternative aspect of the present invention, there is therefore provideda product comprising a Na_(v)1.8 sodium ion channel activity inhibitorand one or more active ingredients as a combined preparation forsimultaneous, separate or sequential use in the treatment or preventionof a Nav1.8 sodium ion channel activity mediated disease, disorder orcondition. Such a combined preparation may be, for example, in the formof a twin pack.

It will be appreciated that for the treatment or prevention of painconditions, pruritic conditions and cough conditions, a compound of thepresent invention may be used in conjunction with another pharmaceuticalagent effective to treat that disease, disorder or condition.

The present invention also provides a method for the treatment orprevention of pain conditions, pruritic conditions and cough conditions,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent effective to threat that disorder,disease or condition, such that together they give effective relief.

The present invention also provides a method for the treatment orprevention of pain conditions, pruritic conditions and cough conditions,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent useful in treating that particularcondition, disorder or disease, such that together they give effectiverelief.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a cell, tissue, system, animal or human that isbeing sought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans, and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a COX-2inhibitor the weight ratio of the compound of the Formula I to the COX-2inhibitor will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of theFormula I and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Methods of Synthesis

The following reaction schemes and Examples illustrate methods which maybe employed for the synthesis of the compounds of structural formula Idescribed in this invention. These reaction schemes and Examples areprovided to illustrate the invention and are not to be construed aslimiting the invention in any manner. All substituents are as definedabove unless indicated otherwise. Several strategies based uponsynthetic transformations known in the literature of organic synthesismay be employed for the preparation of the compounds of structuralformula I. The scope of the invention is defined by the appended claims.

The compounds of the present invention can be prepared according to theprocedures of the following Examples, using appropriate materials. Thecompounds illustrated in the examples are not, however, to be construedas forming the only genus that is considered as the invention. TheExamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of protecting groups, as well as of theconditions and processes of the following preparative procedures, can beused to prepare these compounds. It is also understood that whenever achemical reagent such as a boronic acid or a boronate is notcommercially available, such a chemical reagent can be readily preparedfollowing one of numerous methods described in the literature. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured either by electrospray ion-mass spectroscopy (ESMS)or by atmospheric pressure chemical ionization mass spectroscopy (APCI).

Instrumentation

Reverse phase chromatography was carried out on a Gilson GX-281 equippedwith a column selected from the following: Phenomenexd Synergi C18 (150mm×30 mm×4 micron), YMC-Actus Pro C18 (150 mm×30 mm×5 micron), XtimateC18 (150 mm×25 mm×5 micron), Boston Green ODS (150 mm×30 mm×5 micron),XSELECT C18 (150 mm×30 mm×5 micron), and Waters XSELECT C18 (150 mm×30mm×5 micron). Conditions included either high pH (0-100%acetonitrile/water eluent comprising 0.1% v/v 10 mM NH₄CO₃ or 0.05%NH₄OH) or low pH (0-95% acetonitrile/water eluent comprising 0.1% v/vTFA) and are noted for some examples.

SFC chiral resolution was carried out on a Sepiate Prep SFC 100,Multigram II (MG II), THAR80 prep SFC, or a Waters SFC (80, 200, or 350)using the following conditions: Chiral Method A: AD-H column, 15%ethanol/CO₂; Chiral Method B: AD-H column, 20% IPA/CO₂; Chiral Method C:AS-H column, 20% MeOH/CO₂; Chiral Method D: AD-H column, 20%ethanol/CO₂; Chiral Method E: Lux Cellulose-4 column, 30% ethanol/CO₂;Chiral Method F: IA column, 15% ethanol/CO₂; Chiral Method G: IA column,40% methanol/CO₂; Chiral Method H: AD-H column, 10% methanol/CO₂; ChiralMethod I: AD-H column, 30% ethanol/CO₂; Chiral Method J: AD-H column,40% ethanol/CO₂; and Chiral Method K: IG column, 12% methanol/CO₂.

LC/MS determinations were carried out on a Waters Classing Aquity systemequipped with TUV and MS detectors and a Waters SQD mass spectrometer, aShimadzu 20 UV 254 and 220 nM with Shimadzu 2010 or 2020 massspectrometer, or an Agilent 1200 HPLC quipped with DAD/ELSD and G6110MSD using one of the following conditions: 1) Ascentis Express C18 (3×50mm) 2.7 m column using mobile phase containing A: 0.05% Trifluoroaceticacid in water and B: 0.05% Trifluoroacetic acid in acetonitrile with agradient from 90:10 (A:B) to 5:95 (A:B) over 6 min at a flow rate of 1.8mL/min, UV detection at 210 nm; 2) Aquity BEH C18, (1.0×50 mm) 1.7 mcolumn using mobile phase containing A: 0.05% Trifluoroacetic acid inwater and B: 0.05% Trifluoroacetic acid in acetonitrile with a gradientfrom 90:10 (A:B) to 5:95 (A:B) over 2 min at a flow rate of 0.3 mL/min,UV detection at 215 nm; 3) Agilent YMC J'Sphere H-80 (3×50 mm) 5 mcolumn using mobile phase containing A: 0.1% Trifluoroacetic acid inwater and B: acetonitrile with a gradient from 95:5 (A:B) to 0:100 (A:B)over 3.6 min and 0:100 (A:B) for 0.4 min at a flow rate of 1.4 mL/min,UV detection at 254 and 220 nm and Agilent 1100 quadrupole massspectrometer; 4) an Agilent TC-C18 (2.1×50 mm) 5 m column using mobilephase containing A: 0.0375% Trifluoroacetic acid in water and B:0.01875% Trifluoroacetic acid in acetonitrile with a gradient from 90:10(A:B) for 0.4 min to 90:10 to 0:100 (A:B) over 3 min and 10:90 (A:B) for0.6 min at a flow rate of 0.8 mL/min, UV detection at 254 and 220 nm andAgilent 6110 quadrupole mass spectrometer.

Proton or ¹H NMR was acquired using a Varian Unity-Inova 400 MHz NMRspectrometer equipped with a Varian 400 ATB PFG 5 mm, Nalorac DBG 400-5or a Nalorac IDG 400-5 probe, a Varian-400 MHz MR spectrometer equippedwith an Auto X ID PFG Probe 5 mm, a Varian 400 MHz VNMRS spectrometerequipped with a PFG 4Nuc Probe 5 mm, or a Bruker AvanceIll 500 MHzspectrometer equipped with a PABBO Probe 5 mm in accordance withstandard analytical techniques, unless specified otherwise, and resultsof spectral analysis are reported.

Abbreviations

Throughout the Examples section, the following abbreviations are used toindicate various reagents, substituents and solvents: AcCN isacetonitrile; ACE-Cl is 1-chloroethyl chloroformate; AcOH is aceticacid; BAST is bis(2-methoxyethyl)aminosulfur trifluoride; Boc istert-butoxycarbonyl; Boc₂O is di-tert-butyl carbonate; Brettphos-Pd-G3is[(2-di-cyclo-hexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate; Calc'd is calculated; Cu(OTf)₂ is copper(II)trifluoromethanesulfonate; DBU is 1,8-diazabicyclo-[5.4.0]-undec-7-ene;DCE is dichloroethane; DCM is dichloromethane; DIPEA isdiisopropylamine; DMA is dimethylacetamide; DMAP is4-dimethylaminopyridine; DMB is 2,4-dimethoxybenzyl-; DMF isdimethylformamide; DMSO is dimethylsulfoxide; dppf is1,1′-bis(diphenylphosphino)ferrocene; DTBPF-Pd-G3 ismethanesulfonato(1,1-bis(di-t-butylphosphino)ferrocene)(2′-amino-1,1′-biphenyl-2-yl)palladium(II);EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et₂O is diethylether; EtOAc is ethyl acetate; EtOH is ethanol; g is grams; HATU is1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate;Hex is hexanes; h or hr(s) is hour(s); HPLC is high-performance liquidchromatography; IPA is isopropyl alcohol; L is liter; LAH is lithiumaluminum hydride; LC/MS is liquid chromatography/mass spectrometry; LRMSis low resolution mass spectrometry; Me is methyl; MeCN is acetonitrile;MeOH is methanol; MTBE is methyl tert-butyl ether; mg is milligrams; mLis milliliter; mmol is millimolar; M is molar; NBS isN-bromosuccinimide; NCS is N-chlorosuccinimide; NIS isN-iodosuccinimide; NMP is N-methylpyrrolidone; Pd/C is palladium oncarbon; Pd₂(dba)₃ is tris(dibenzylidene-acetone)-dipalladium(0);Pd(PPh₃)₄ is tetrakis(triphenylphosphine)-palladium(0); Pd(dppf)Cl₂ is[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II); Pd(tBu₃P)₂is bis(tri-tert-butyl-phosphine)palladium(0); PE is petroleum ether; PGis protecting group; POCl₃ is phosphorus(V)oxychloride; P(tBu)₃—Pd-G2 ischloro[(tri-tert-butylphosphine)-2-(2-amino-biphenyl)] palladium(II);prep is preparative; PyBOP isbenzotriazol-1-yl-oxytri-pyrrolidino-phosphonium hexafluorophosphate;RuPhos-Pd-G2 ischloro(2-dicyclohexyl-phosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II);Ruphos Pd G3 or Ruphos-Pd-G3 is(2-Dicyclohexyl-phosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II)methanesulfonate; r.t. or rt or RT is room temperature; SFC isSupercritical Fluid Chromatography; TEA is triethylamine; t-BuONa issodium tert-butoxide; THF is tetrahydrofuran; TFA is trifluoroaceticacid; TMSCl is trimethylsilyl chloride; UV is ultraviolet; XantPhos PdG2 or XantPhos-Pd-G2 ischloro[(4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene)-2-(2′-amino-1,1′-biphenyl)]-palladium(II);Xantphos G3 or XantPhos-Pd-G3 is[(4,5-Bis-(diphenyl-phosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]-palladium(II)methane-sulfonate; XantPhos is4,5-Bis(diphenylphosphino)-9,9-dimethyl-xanthene; t-BuXPhos Pd G3, tBuXphos Pd G3, t-Bu Xphos-Pd-G3 or tBuXphos-Pd-G3 is[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; tBuXPhos is2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; and Xphos-Pd-G2ischloro-(2-di-cyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II).

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare either commercially available or made by known procedures in theliterature or as illustrated. The present invention further providesprocesses for the preparation of compounds of structural formula I asdefined above. In some cases the order of carrying out the foregoingreaction schemes may be varied to facilitate the reaction or to avoidunwanted reaction products. The following examples are provided for thepurpose of illustration only and are not to be construed as limitationson the disclosed invention.

As illustrated in Scheme A, in general, compounds of the invention canbe prepared by nucleophilic aromatic substitution between anappropriately functionalized carboxylic acid A-1 and an amine A-2, underbasic conditions using a base such as DIPEA, to afford intermediate A-3.Intermediate A-3 can then be transformed into a primary carboxamide A-4which can be coupled to an appropriately functionalized heteroarylhalide A-5 to provide compounds of Formula A-5. In some embodiments aprotecting group such as 2,4-dimethoxybenzyl (DMB), tert-butyl or Bocmay need to be removed after the C—N coupling to afford the compound ofFormula A-6. Amines of type A-2 and heteroaryl halides of type A-5 arecommercially available or may be synthesized from appropriateintermediates.

The nucleophilic aromatic substitution may also occur in the presence ofthe carboxamide A-4, or alternative functional groups that can beconverted to the carboxamide A-4 such as a halide, ester or cyanofunctional group, before being coupled to a heteroaryl halide A-5 toprovide compounds of Formula A-6. Hydrolysis of ester B-1 to give thecarboxylic acid A-3 allows direct amide coupling with an appropriatelyfunctionalized heteroarylamine B-2, by using amide coupling agents suchas EDC or by forming the acid chloride from POCl₃, to afford compoundsof Formula A-6.

Those of skill in the art will appreciate that the amide coupling canoccur first on an appropriately functionalized carboxylic acid (A-1)with a heteroaryl amine B-2, preferably using amide coupling agents suchas EDC or by forming the acid chloride from POCl₃, or a C—N couplingbetween primary carboxamide C-2 and heteroaryl halide A-5 to affordintermediates of type C-1. Intermediates of type C-1 can undergonucleophilic aromatic substitution reactions with secondary amines A-2by displacing a heteroaryl chloride in the presence of a base, such asK₂CO₃ or DIPEA, or cross electrophile coupling reactions with alkylhalides to yield a compound of Formula A-6 as shown in Scheme C.

The compound of Formula A-6 may also be prepared via reaction ofheteroaryl chloride with an amine A-2, followed by halogenation of theadjacent position of the heteroaryl ring D-2. The heteroaryl halide D-2,such as a heteroaryl bromide, can be converted to a nitrile, which canbe hydrolyzed to give a primary carboxamide A-4 and then coupled to aheteroaryl halide A-5 to afford compounds of Formula A-6. Alternatively,halide D-2 can be converted directly into amide A-6 via carbonylation inthe presence of carbon monoxide and a catalyst, such as palladium. Theresulting adduct may need to be deprotected using standard conditions toafford compounds of Formula A-6.

INTERMEDIATES Intermediate 16-chloro-N,N-bis(2,4-dimethoxybenzyl)pyrazine-2-sulfonamide

Step 1: 2-(benzylthio)-6-chloropyrazine

To a solution of 2,6-dichloropyrazine (2.0 g, 13 mmol) in DMF (30 mL)was added K₂CO₃ (1.7 g, 12 mmol) and phenylmethanethiol (1.7 g, 13mmol). The mixture was stirred at 30° C. for 13 hours, then diluted withwater, extracted with EtOAc. The organic phase was separated, washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thetitle compound.

Step 2: 6-chloropyrazine-2-sulfonyl chloride

A solution of 2-(benzylthio)-6-chloropyrazine (1 g crude) in CCl₄ (40mL) and water (10 mL) was cooled 0° C., and then dichlorine (0.30 g, 4.2mmol) was bubbled through the solution at 0° C. for 30 min. Theresulting mixture was diluted with water and extracted with DCM. Theorganic phase was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated to give the title compound.

Step 3: 6-chloro-N,N-bis(2,4-dimethoxybenzyl)pyrazine-2-sulfonamide

To a solution of bis(2,4-dimethoxybenzyl)amine (0.45 g, 1.4 mmol) in DCM(8 mL) was added triethylamine (0.21 g, 2.1 mmol) and6-chloropyrazine-2-sulfonyl chloride (0.30 g crude). The mixture wasstirred at 29° C. for 1 hour, then concentrated and purified by silicagel chromatography (0-18% petroleum ether/EtOAc) to give the titlecompound.

Intermediate 25-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-3-sulfonamide

A mixture of bis(2,4-dimethoxybenzyl)amine (0.99 g, 3.1 mmol) in DCM (3mL) and Et₃N (0.65 mL, 4.7 mmol) was stirred at 25° C. for 5 min, then5-bromopyridine-3-sulfonyl chloride (0.80 g, 3.1 mmol) was added. Themixture was stirred at 25° C. for 1 hour, then purified by silica gelchromatography (petroleum ether) to give the title compound.

Intermediate 3 3-bromo-5-(methylsulfonyl)pyridine

To a solution of 3-bromo-5-(methylthio)pyridine (0.20 g, 0.98 mmol) inDCM (5 mL) was added 3-chlorobenzoperoxoic acid (0.51 g, 2.9 mmol)slowly. The mixture was stirred at 21° C. for 13 hours, then dilutedwith DCM, and quenched with 1N NaOH solution. The organic phase wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the title compound.

Intermediate 44-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide

Step 1: 2-(benzylthio)-4-bromopyridine

To a mixture of sodium hydride (32 g, 0.8 mol) in tetrahydrofuran (1.4L) was added dropwise phenylmethanethiol (99 g, 0.8 mol) with stirringat 0° C. The mixture was stirred at 0° C. for 2 h, then a solution of4-bromo-2-fluoropyridine (140 g, 0.8 mol) in tetrahydrofuran (1.4 L) wasadded to the mixture dropwise with stirring at 0° C. The resultingmixture was stirred at room temperature for 2 h, then cooled to 10° C.,and quenched by the addition of water and extracted with ethyl acetate.The combined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (10% ethyl acetate/petroleumether) to give the title compound.

Step 2: 4-bromopyridine-2-sulfonyl chloride

To a solution of 2-(benzylthio)-4-bromopyridine (200 g, 0.72 mol) in DCM(2.8 L), AcOH (0.4 L) and water (0.8 L) was added1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (424 g, 2.2 mol)dropwise with stirring at 0° C. The mixture was stirred at roomtemperature for 16 hours. Then the mixture was quenched with water andextracted with DCM. The combined organic layers were washed with sodiumbicarbonate, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to give a residue that was wasslurried with 3 volumes of PE and filtered to give the title compound.

Step 3: 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide

To a solution of 4-bromo-pyridine-2-sulfonyl chloride (90 g, 0.35 mol)in DCM (1.8 L) was added DIPEA (0.18 L, 1.1 mol), followed by theportionwise addition of bis(2,4-dimethoxybenzyl)amine (56 g, 0.18 mol).The mixture was stirred at 20° C. for 1.5 h, then diluted with water andextracted with DCM. The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (10% ethyl acetate/petroleumether) to give the title compound.

Intermediate 54-amino-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide

Step 1: 2-(benzylthio)-4-iodopyridine

To a mixture of sodium hydride (54 g, 1.3 mol) in tetrahydrofuran (3.0L) was added phenylmethanethiol (54 g, 1.3 mol) dropwise with stirringat 0° C. The mixture was stirred at 0° C. for 2 hours. To the mixturewas added a solution of 2-fluoro-4-iodopyridine (300 g, 1.3 mol) intetrahydrofuran (3.0 L) dropwise with stirring at 0° C. The resultingmixture was stirred at room temperature for 2 h, then cooled to 10° C.,quenched by the addition of water and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (10% ethyl acetate/petroleumether) to give the title compound.

Step 2: 4-iodopyridine-2-sulfonyl chloride

To a solution of a 2-(benzylthio)-4-iodopyridine (430 g, 1.3 mol) in DCM(6.0 L), AcOH (0.86 L) and water (1.7 L) was added1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (780 g, 3.9 mol)dropwise with stirring at 0° C. The mixture was stirred at roomtemperature for 16 h, then quenched with water and extracted with DCM.The combined organic layers were washed with sodium bicarbonate, driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure to give a residue that was was slurried with 3 volumesof PE and filtered to give the title compound.

Step 3: N, N-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide

To a solution of 4-iodopyridine-2-sulfonyl chloride (250 g, 0.82 mol) inDCM (5.0 L) under an atmosphere of nitrogen was added DIPEA (0.43 L, 2.5mol), then bis(2,4-dimethoxybenzyl)amine (130 g, 0.41 mol) portionwise.The mixture was stirred at 20° C. for 1.5 h, then diluted with water andextracted with DCM. The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (10% ethyl acetate/petroleumether) to give the title compound.

Step 4: 4-amino-N,N-bis(2,4dimethoxybenzyl)pyridine-2-sulfonamide

To a solution ofN,N-bis(2,4-dimethoxybenzyl)-4-iodopyridine-2-sulfonamide (70 g, 0.12mol) in NMP (1.4 L) under an atmosphere of nitrogen was added ammoniumacetate (92 g, 1.2 mol), copper(II) acetylacetonate (9.4 g, 0.036 mol),2-acetylcyclohexanone (10 g, 0.072 mol) and Cs₂CO₃ (120 g, 0.36 mol) atroom temperature. The mixture was stirred at 90° C. for 16 hours. Thenthe mixture was quenched with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give aresidue that was slurried with 3 volumes of MTBE, then concentrated andrecrystallized from acetonitrile to give the title compound.

Intermediate 6 tert-butyltert-butyl((4-chloropyridin-2-yl)sulfonyl)carbamate

Step 1: 2-(benzylthio)-4-chloropyridine

To a mixture of 2-bromo-4-chloropyridine (10 g, 52 mmol) in dioxane (150mL) was added XantPhos (4.5 g, 7.8 mmol), DIPEA (18 mL, 100 mmol),Pd₂(dba)₃ (2.4 g, 2.6 mmol) and phenylmethanethiol (6.1 mL, 52 mmol).The mixture was stirred at 100° C. for 13 h, then diluted in water andextracted with EtOAc. The combined organic layers were concentratedunder reduced pressure to give a residue that was purified by silica gelchromatography (0-2% EtOAc/petroleum ether) to give the title compound.

Step 2: 4-chloropyridine-2-sulfonamide

To a solution of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (22 g,110 mmol) in acetonitrile (40 mL) at 0° C. was added acetic acid (4.0mL) and water (3.2 mL). The mixture was stirred at 0° C. for 5 min, then2-(benzylthio)-4-chloropyridine (10 g, 45 mmol) was added. The mixturewas stirred at 0° C. for 0.5 h, then NH₄OH (56 g, 450 mmol) was added.The mixture was stirred at 0° C. for 0.5 h, then diluted in water andextracted with EtOAc. The organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (50% EtOAc/petroleum ether) togive the title compound.

Step 3: tert-butyl tert-butyl((4-chloropyridin-2-yl)sulfonyl) carbamate

To a mixture of 4-chloropyridine-2-sulfonamide (1.2 g, 6.2 mmol) in THF(40 mL) was added Boc₂O (3.2 mL, 14 mmol) and DMAP (0.76 g, 6.2 mmol) at25° C. The mixture was stirred at 80° C. for 16 h. Then the mixture wasconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (20% EtOAc/petroleum ether) to give thetitle compound.

Intermediate 7 tert-butyl((4-bromopyridin-2-yl)sulfonyl)(tert-butyl)carbamate

Step 1: 4-bromopyridine-2-sulfonamide

To a solution of 4-bromopyridine-2-sulfonyl chloride (300 g, 1.3 mol) inacetonitrile (3.0 L) at 0° C. was added NH₄OH (1.5 kg, 13 mol) dropwisewith stirring. The mixture was stirred at room temperature for 3 h, thenquenched with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas slurried with DCM to give the title compound.

Step 2: tert-butyl ((4-bromopyridin-2-yl)-sulfonyl)(tert-butyl)carbamate

To a mixture of 4-bromopyridine-2-sulfonamide (50 g, 0.21 mol) in2-methyltetrahydrofuran (1.0 L) at 25° C. was added Boc₂O (230 g, 1.1mol) and DMAP (26 g, 0.21 mol). The mixture was stirred at 25° C. for0.5 hour, then the mixture was stirred at 70° C. for 16 hours. Themixture was then cooled to 15° C., quenched with water and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (1:30-1:24 ethyl acetate/petroleum ether), and thenslurried with n-hexane to give the title compound.

Intermediate 8 tert-butyl((4-aminopyridin-2-yl)sulfonyl)(tert-butyl)carbamate

Step 1: 4-iodopyridine-2-sulfonamide

To a solution of 4-iodopyridine-2-sulfonyl chloride (550 g, 1.8 mol) inacetonitrile (11.0 L) at 0° C. was added NH₄OH (2.1 kg, 18 mol) dropwisewith stirring. The mixture was stirred at room temperature for 3 h, thenquenched with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas slurried with DCM to give the title compound.

Step 2: tert-butyl tert-butyl((4-iodopyridin-yl) sulfonyl)carbamate

To a mixture of 4-iodopyridine-2-sulfonamide (125 g, 0.44 mol) in2-methyltetrahydrofuran (2.5 L) at 25° C. was added Boc₂O (480 g, 2.2mol) and DMAP (11 g, 0.088 mol). The mixture was stirred at 25° C. for0.5 hour, then the mixture was stirred at 70° C. for 16 hours. Themixture was then cooled to 15° C., quenched with water and extractedwith ethyl acetate. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (1:30-1:24 ethyl acetate/petroleum ether) to give thetitle compound.

Step 3: tert-butyl ((4-aminopyridin-2-yl)sulfonyl)(tertbutyl)carbamate

To a solution of tert-butyltert-butyl((4-iodopyridin-2-yl)sulfonyl)carbamate (50 g, 0.11 mol) inDMF (1.0 L) under an atmosphere of nitrogen was added NH₄OH (64 g, 0.57mol), copper(II) acetylacetonate (8.9 g, 0.033 mol),2-acetylcyclohexanone (9.6 g, 0.066 mol) and Cs₂CO₃ (37 g, 0.11 mol) atroom temperature. The mixture was stirred at 60° C. for 16 h, thenquenched with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to give a residue that wasslurried with petroleum ether to give the title compound.

Intermediate 9 5,5-difluoroazepan-2-one

Step 1: tert-butyl (3-carbamoyl-1,2,4-oxadiazol-5-yl)carbamate

Ammonia gas was bubbled through a solution of ethyl5-((tert-butoxycarbonyl)amino)-1,2,4-oxadiazole-3-carboxylate (0.10 g,0.39 mmol) in EtOH (3 mL) at 20° C. for 15 minutes. The mixture wasstirred at 20° C. for 1 hour, then concentrated under reduced pressureto give the title compound.

Step 2: 5-amino-1,2,4-oxadiazole-3-carbonitrile

To a solution of tert-butyl (3-carbamoyl-1,2,4-oxadiazol-5-yl)carbamate(20 mg, 0.088 mmol) in DCM (2 mL) at 20° C. was added phosphoryltrichloride (27 mg, 0.17 mmol) and a drop of DMF. The mixture wasstirred at 40° C. for 1 h. Then the mixture was cooled to rt, dilutedwith water, treated with 2N NaOH to pH=8 and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound.

Intermediate 10 (R and S)-4,4-difluoro-5-methylazepane Hydrochloride

Step 1: 1-(tert-butyl) 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate

To a solution of 1-(tert-butyl) 4-ethyl 5-oxoazepane-1,4-dicarboxylate(1.0 g, 3.50 mmol) in DMF (12 mL) was added NaH (0.14 g, 3.5 mmol) at 0°C. over 1 min. After stirring for 1 h at 0° C., MeI (0.79 mL, 13 mmol)was added to the mixture at 0° C. The mixture was stirred at 20° C. for2 h, then quenched with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-4% ethyl acetate/petroleumether) to give the title compound.

Step 2: tert-butyl 4-methyl-5-oxoazepane-1-carboxylate

A mixture of KOH (4.2 mL, 8.3 mmol) and 1-(tert-butyl) 4-ethyl4-methyl-5-oxoazepane-1,4-dicarboxylate (0.50 g, 1.7 mmol) in dioxane (5mL) was stirred at 100° C. for 12 h. The mixture was quenched with waterand extracted with EtOAc. The organic layer was separated, washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound.

Step 3: tert-butyl 4,4-difluoro-5-methylazepane-1-carboxylate

A mixture of tert-butyl 4-methyl-5-oxoazepane-1-carboxylate (0.37 g, 1.6mmol) and BAST (0.90 mL, 4.9 mmol) in CHCl₃ (5 mL) was degassed andbackfilled with nitrogen three times. The mixture was heated to 55° C.for 12 h, then quenched with water and extracted with EtOAc. The organiclayer was separated, washed with brine, concentrated and filtered underreduced pressure to give a residue that was purified by silica gelchromatography (0-4% petroleum ether/ethyl acetate) to give the titlecompound.

Step 4: (R and S)-4,4-difluoro-5-methylazepane Hydrochloride

A mixture of tert-butyl 4,4-difluoro-5-methylazepane-1-carboxylate (0.30g, 1.2 mmol) in MeOH (2 mL) and HCl/dioxane (2 mL) was stirred at 20° C.for 12 h. Then the mixture was concentrated under reduced pressure togive the title compound.

Intermediate 11 4,4-Dichloro-3-methylpiperidine Hydrochloride

Step 1: Benzyl 4,4-dichloro-3-methylpiperidine-1-carboxylate

Tungsten(VI) chloride (1.6 g, 4.1 mmol) was added to a solution ofbenzyl 3-methyl-4-oxopiperidine-1-carboxylate (0.34 g, 1.4 mmol) in DCM(16 mL). The mixture was heated at 40° C. for 10 minutes, then quenchedwith aqueous sodium hydrogen carbonate (saturated) and extracted withdichloromethane. The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-100% EtOAc/hexanes) to givethe title compound.

Step 2: 4,4-Dichloro-3-methylpiperidine Hydrochloride

A solution of benzyl 4,4-dichloro-3-methylpiperidine-1-carboxylate (0.39g, 1.3 mmol) in EtOH was added to a suspension of Pd—C (0.14 g, 0.13mmol) in nitrogen degassed EtOH (13 mL total). The mixture was evacuatedand backfilled with hydrogen, and then stirred under a balloon ofhydrogen for 1 hour. The reaction mixture was purged with nitrogen, andthen filtered through a pad of Celite™. The filtrate was treated with 4MHCl (1.6 mL, 6.4 mmol) in dioxane, stirred for 10 minutes, and thenconcentrated under reduced pressure to give the title compound.

Intermediate 12 4,4-Dichloroazepane Hydrochloride

Step 1: Benzyl 4,4-dichloroazepane-1-carboxylate

Tungsten(VI) chloride (1.2 g, 3.1 mmol) was added to a solution ofbenzyl 4-oxoazepane-1-carboxylate (0.26 g, 1.0 mmol) in DCM (10 mL). Themixture was heated at 40° C. for 10 minutes, then quenched with aqueoussodium hydrogen carbonate (saturated) and extracted withdichloromethane. The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-100% EtOAc/hexanes) to givethe title compound.

Step 2: 4,4-Dichloroazepane Hydrochloride

A solution of benzyl 4,4-dichloroazepane-1-carboxylate (0.12 g, 0.40mmol) in EtOH was added to a suspension of Pd—C (43 mg, 0.040 mmol) innitrogen degassed EtOH (4 mL total). The mixture was evacuated andbackfilled with hydrogen, then stirred under a balloon of hydrogen for 1hour. The mixture was purged with nitrogen, and then filtered through apad of Celite™. The filtrate was treated with 4M HCl (0.50 mL, 2.0 mmol)in dioxane, stirred for 10 minutes, and then concentrated under reducedpressure to give the title compound.

Intermediate 13 (R)-2-(trifluoromethyl)-1,4-oxazepane hydrobromide

Step 1: (R)-3-((3,3,3-trifluoro-2-hydroxypropyl)amino)propan-1-ol

(R)-2-(trifluoro-methyl)oxirane (3.7 g, 33 mmol) was added to a stirredsolution of 3-amino-1-propanol (2.5 g, 33 mmol) in THF (33 mL) at 0° C.The mixture was stirred at 0° C. for 1 hour, then warmed to ambienttemperature for 16 hours. Then the mixture was concentrated andazeotroped with THF to give the title compound.

Step 2:(R)—N-(3-hydroxypropyl)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide

Tosyl-Cl (6.7 g, 35 mmol) was added to a solution of(R)-3-((3,3,3-trifluoro-2-hydroxypropyl)amino)propan-1-ol (6.0 g, 32mmol) and TEA (8.9 mL, 64 mmol) in dichloromethane (80 mL) at 0° C. Themixture was stirred at 0° C. for 1 hour, then warmed to ambienttemperature for 16 hours. The mixture was then diluted with EtOAc. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-100% EtOAc/hexanes) to givethe title compound.

Step 3: (R)-4-tosyl-2-(trifluoromethyl)-1,4-oxazepane

To a stirred solution of(R)—N-(3-hydroxypropyl)-4-methyl-N-(3,3,3-trifluoro-2-hydroxypropyl)benzenesulfonamide(4.0 g, 12 mmol) in THF (120 mL) at 0° C. was added sodium hydride (1.2g, 29 mmol). The mixture was stirred 5 minutes, then treated with1-(p-toluenesulfonyl)imidazole (2.6 g, 12 mmol) at 0° C. The resultingmixture was warmed to ambient temperature for 16 hours, then quenchedwith water and extracted with EtOAc. The organic layer was separated,washed with brine, dried over MgSO₄, filtered and concentrated to give aresidue that was purified by column chromatography (0-100%EtOAc/hexanes) to give the title compound.

Step 4: (R)-2-(trifluoromethyl)-1,4-oxazepane hydrobromide

To a mixture of (R)-4-tosyl-2-(trifluoromethyl)-1,4-oxazepane (3.0 g,9.3 mmol) and phenol (1.6 mL, 19 mmol) at room temperature was added HBrin AcOH (1.7 mL, 9.3 mmol). The mixture was heated to 80° C. for 6hours. Then the mixture was cooled to ambient temperature, concentratedunder reduced pressure and azeotroped with toluene. The resultingresidue was trituated with Et₂O, collected by filtration, washed withEt₂O and dried under reduced pressure to give the title compound.

Intermediate 14 (2S,6R)-2-methyl-6-(trifluoromethyl)morpholineHydrochloride

Step 1: (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol

To a solution of lithium trifluoromethanesulfonate (1.4 g, 9.2 mmol) inacetonitrile (23 mL) was added (R)-(+)-3,3,3-trifluoro-1,2-epoxypropane(5.5 g, 49 mmol) slowly at −10° C. After 5 minutes, benzylamine (5.1 mL,47 mmol) was added slowly. The reaction mixture was stirred at ambienttemperature for 18 hours. Then the mixture was concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (0-100% EtOAc/hexanes) to give the title compound.

Step 2:N-benzyl-2-bromo-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide

To a solution of (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (3.0 g,14 mmol) in DCM (55 mL) was added TEA (2.5 mL, 18 mmol), followed by2-bromopropionyl chloride (1.5 mL, 15 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 30 minutes, then warmed to ambienttemperature for 4 hours. Then the mixture was concentrated under reducedpressure. The resulting residue was suspended in EtOAc, filtered througha pad of silica gel, washed with EtOAc, and concentrated under reducedpressure to give the title compound.

Step 3: (6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one

To a stirred solution ofN-benzyl-2-bromo-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide (4.0g, 11 mmol) in THF (45 mL) at 0° C. was added portionwise NaH (0.68 g,17 mmol). The mixture was warmed to ambient temperature and stirred for3 hours. Then the mixture was diluted with ½ saturated brine andextracted with DCM. The combined organic layers were filtered through apad of Celite™, washing with dichloromethane, and concentrated to give aresidue that was purified by silica gel chromatography (0-50%EtOAc/hexanes) to give the title compound.

Step 4: (2S,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine

To a solution of(6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (3.0 g, 11mmol) in THF (55 mL) at ambient temperature was added LAH (11 mL, 22mmol) portionwise over 20 minutes. The reaction mixture was heated toreflux for 1 hour, then cooled to rt. The mixture was then diluted withether, cooled to 0° C. and slowly treated with water (0.9 mL), followedby 15% aqueous sodium hydroxide (0.9 mL), and then water (2.7 mL). Thenmixture was warmed to ambient temperature with stirring for 15 minutes,then treated with anhydrous magnesium sulfate and stirred for 1 hour.The resulting mixture was filtered to remove solids, and the filter cakewas washed with Et₂O. The filtrate was concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (0-100% EtOAc/hexanes) to give the title compound.

Step 5: (2S,6R)-2-methyl-6-(trifluoromethyl)morpholine Hydrochloride

To a stirred solution of(2S,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine (0.30 g, 1.2mmol) in DCE (1.2 mL) was added ACE-Cl (0.13 mL, 1.2 mmol). The mixturewas heated to reflux for 16 hours, then cooled to rt and concentratedunder reduced pressure to give a residue that was dissolved in MeOH (1.2mL). The resulting mixture was heated to reflux for 4 hours. Then themixture was cooled to ambient temperature and concentrated to give aresidue that was triturated with Et₂O:hexanes (˜1:3) to give a solid.The solid was filtered, collected and dried under reduced pressure togive the title compound.

Intermediate 15 (2R,6S and 2S,6R)-2-ethyl-6-(trifluoromethyl)morpholineHydrochloride

Step 1: N-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)butanamide

To a solution of 3-(benzylamino)-1,1,1-trifluoropropan-2-ol (1.2 g, 5.2mmol) and TEA (2.2 mL, 16 mmol) in dichloromethane (25 mL) was addeddropwise 2-bromobutanoyl chloride (1.0 g, 5.4 mmol) at 0° C. The mixturewas stirred at 0° C. for 5 min then warmed to 15° C. for 1 hour. Themixture was concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (18-25% ethylacetate/petroleum ether) to give the title compound.

Step 2: 4-benzyl-2-ethyl-6-(trifluoromethyl)morpholin-3-one

To a stirred suspension of NaH (0.17 g, 4.2 mmol) in THF (10 mL) at 0°C. was added a solution ofN-benzyl-2-bromo-N-(3,3,3-trifluoro-2-hydroxypropyl)butanamide (1.4 g,3.8 mmol) in THF (5 mL). The mixture was stirred at room temperature for1 hour. The mixture was cooled to 0° C. and treated with MeOH (0.5 mL)until no more gas evolved. The mixture was concentrated under reducedpressure to a residue that was dissolved in water and extracted withEtOAc. The organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound.

Step 3: (2R,6S and 2S,6R)-4-benzyl-2-ethyl-6-(trifluoromethyl)morpholine

To a stirred solution of4-benzyl-2-ethyl-6-(trifluoromethyl)morpholin-3-one (1.2 g) in THF (5mL) at 0° C. was added dropwise BH₃-THF (21 mL, 21 mmol). The mixturewas heated to 80° C. for 12 hours, then cooled to rt and quenched by thedropwise addition of MeOH (5 mL). The reaction mixture was concentratedunder reduced pressure. The resulting residue was dissolved in MeOH (50mL) and refluxed for 1 hour. Then the mixture was concentrated underreduced pressure to give a residue that was purified by silica gelchromatography to give the title compound.

Step 4: (2R,6S and 2S,6R)-2-ethyl-6-(trifluoromethyl)morpholineHydrochloride

To a solution of (2R,6S and2S,6R)-4-benzyl-2-ethyl-6-(trifluoromethyl)morpholine (0.40 g, 1.5 mmol)in THF (10 mL) under an atmosphere of nitrogen was added Pd/C (0.078 g,0.073 mmol). The mixture was degassed and backfilled with hydrogen(three times). Then the mixture was stirred under hydrogen (50 psi) at20° C. for 12 hours. The reaction mixture was filtered, and the filtratewas treated with HCl/EtOAc and concentrated under reduced pressure togive the title compound.

Intermediate 16 2,2-dimethyl-6-(trifluoromethyl)morpholine Hydrochloride

Step 1: 3-(benzyl(2-methylallyl)amino)-1,1,1-trifluoropropan-2-ol

To a mixture of 3-(benzylamino)-1,1,1-trifluoropropan-2-ol (2.2 g, 10mmol), K₂CO₃ (2.8 g, 20 mmol) in THF (20 mL) was added3-bromo-2-methylprop-1-ene (1.8 g, 13 mmol) at 20° C. The mixture wasstirred at 20° C. for 16 hours, then filtered. The filtrate wasconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (5% ethyl acetate/petroleum ether) to givethe title compound.

Step 2: 4-benzyl-2,2-dimethyl-6-(trifluoromethyl)morpholine

To a solution of Hg(OAc)₂ (0.50 g, 1.6 mmol) in THF (5 mL) and water (5mL) was added 3-(benzyl(2-methylallyl)amino)-1,1,1-trifluoropropan-2-ol(0.42 g, 1.5 mmol). The mixture was stirred at 15° C. for 3 hours. Thenthe mixture was treated with NaOH (1.2 mL, 3.1 mmol, 2.5 M in water),followed by NaBH₄ (67 mg, 1.8 mmol). The reaction mixture was stirred at15° C. for 16 h, then extracted with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue that was purified by silica gel chromatography (3%ethyl acetate/petroleum ether) to give the title compound.

Step 3: 2,2-dimethyl-6-(trifluoromethyl)morpholine Hydrochloride

To a solution of 4-benzyl-2,2-dimethyl-6-(trifluoromethyl)morpholine(0.25 g, 0.92 mmol) in THF (5 mL) under an atmosphere of nitrogen wasadded Pd/C (49 mg). The mixture was degassed and backfilled withhydrogen (three times). The reaction mixture was stirred under hydrogen(55 psi) at 15° C. for 12 hours, then filtered. The filtrate was treatedwith HCl/EtOAc (1 mL), and then concentrated under reduced pressure togive the title compound.

Intermediate 17 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinic acid

To a mixture of 2-chloro-5-(trifluoromethyl)nicotinic acid (0.50 g, 2.2mmol) in DMF (10 mL) was added K₂CO₃ (0.92 g, 6.6 mmol) andhexamethyleneimine (0.26 g, 2.7 mmol). The mixture was stirred atambient temperature for 16 hours. Then the mixture was diluted withEtOAc, washed with 5% aqueous AcOH and brine, then dried over MgSO₄,filtered and concentrated to give the title compound.

Intermediate 18 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinic acid (0.20g, 0.69 mmol) in DMF (8 mL) was added triethylamine (0.19 mL, 1.4 mmol),HATU (0.32 g, 0.83 mmol) and ammonia hydrochloride (56 mg, 1.0 mmol).The mixture was stirred at 30° C. for 12 hours, then diluted with waterand extracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give a residuethat was purified by silica gel chromatography (50% petroleumether/EtOAc) to give the title compound.

Intermediate 19 2-chloro-5-(trifluoromethyl)nicotinamide

A mixture of (COCl)₂ (0.093 mL, 1.1 mmol) and2-chloro-5-(trifluoromethyl)nicotinic acid (200 mg, 0.89 mmol) in DCM(10 mL) was stirred at 0° C. for 2 h. Then the mixture was concentratedunder reduced pressure, dissolved in THF (10 mL) and treated withNH₃—H₂O (5.0 mL, 36 mmol) at 20° C. for 2 h. The mixture was extractedwith EtOAc and the combined organic layers were washed with water,brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound.

Intermediate 202-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide

Step 1:3-bromo-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)pyridine

To a solution of 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (48 g, 180mmol) and 4,4-difluoropiperidine hydrochloride (36 g, 230 mmol) in NMPwas added triethylamine (47 g, 460 mmol). The mixture was heated to 100°C. for 1 h, then cooled to rt and diluted in EtOAc. The organic layerwas washed with water, citric acid, then brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinonitrile

To a solution of3-bromo-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)pyridine (40g, 120 mmol) in degassed DMA (400 mL) was added allylpalladium(II)chloride (1.3 g, 3.5 mmol), Xantphos (4.0 g, 7.0 mmol) and potassiumferrocyanide (20 g, 46 mmol). The mixture was heated to 100° C. for 16hours, then filtered through diatomite with rinsed with EtOAc. Thefiltrate was washed with water, dried over Na₂SO₄ and concentrated togive a residue that was purified by silica gel chromatography (0-10%EtOAc/petroleum ether) to give the title compound.

Step 3: 2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinonitrile (35 g,120 mmol) in DCE under an atmosphere of nitrogen was added Cu(OTf)₂,followed by N,N-diethylhydroxylamine and trifluoromethanesulfonic acid.The mixture was heated to 50° C. for 2 h, then quenched into water andextracted with DCM. The organic layers were washed with citric acid thenbrine, dried over Na₂SO₄, filtered and concentrated to give a residuethat was slurried in 1:1 Et₂O and petroleum ether and filtered to givethe title compound.

Intermediate 212-chloro-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1: tert-butyltert-butyl((4-(2-chloro-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid(0.81 g, 3.6 mmol) and tert-butyl(4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (1.2 g, 3.6 mmol) inpyridine (18 mL) at 0° C. was added POCl₃ (0.37 mL, 3.9 mmol). Themixture was stirred at 0° C. for 1 hour, then quenched with brine(saturated), and extracted with ethyl acetate. The organic phase wasdried over MgSO₄, filtered and concentrated under reduced pressure togive a residue that was purified on silica gel, eluting with a gradientof 0-100% EtOAc/hexanes over 15 column volumes, to give the titlecompound.

Step 2:2-chloro-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a stirred solution of tert-butyltert-butyl((4-(2-chloro-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(1.7 g, 3.1 mmol) in DCM (25 mL) at 0° C. was added TFA (6.3 mL). Themixture was warmed to room temperature and stirred for 4 hours, thenconcentrated under reduced pressure. The resulting residue was dissolvedin EtOAc. The organic phase was separated, washed with saturated aqueousNaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure. The resulting residue was heated to 80° C. in EtOAc, thencooled to rt.

The resulting solid filtered to give the title compound.

Intermediate 22N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-5-(trifluoromethyl)nicotinamide

To a solution of 2-chloro-5-(trifluoromethyl)nicotinic acid (0.20 g,0.89 mmol) and4-amino-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (0.42 g, 0.89mmol) in pyridine (1.0 mL) was added POCl₃ (0.083 mL, 0.89 mmol) at 0°C. The mixture was stirred at 0° C. for 10 minutes, then quenched withwater and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give aresidue that was purified by silica gel chromatography (25-30% ethylacetate/petroleum ether) to give the title compound.

Intermediate 232-(4,4-Dichloropiperidin-1-yl)-5-(trifluoromethyl)nicotinic acid

Step 1: Methyl 2-(4-oxopiperidin-1-yl)-5-(trifluoromethyl)nicotinate

A mixture of methyl 2-chloro-5-(trifluoromethyl)nicotinate (0.27 g, 1.1mmol), piperidin-4-one hydrochloride (0.15 g, 1.1 mmol) and DIPEA (0.59mL, 3.4 mmol) in NMP (5.6 mL) was heated at 70° C. for 16 hours. Thenthe reaction mixture was quenched with aqueous potassium phosphatemonobasic (saturated) and extracted with ethyl acetate. The combinedorganic layers were dried over MgSO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (0-100% EtOAc/hexanes) to give the title compound.

Step 2: Methyl2-(4,4-dichloropiperidin-1-yl)-5-(trifluoromethyl)nicotinate

Tungsten(VI) chloride (1.2 g, 2.8 mmol) was added to a solution ofmethyl 2-(4-oxopiperidin-1-yl)-5-(trifluoromethyl)nicotinate (0.29 g,0.95 mmol) in DCM (19 mL). The mixture was heated at 40° C. for 10minutes, then diluted with DCM. The organic layer was separated, washedwith saturated aqueous NaHCO₃ solution. dried over MgSO₄, filtered andconcentrated under reduced pressure to give the title compound.

Step 3: 2-(4,4-Dichloropiperidin-1-yl)-5-(trifluoromethyl)nicotinic acid

To a solution of methyl2-(4,4-dichloropiperidin-1-yl)-5-(trifluoromethyl)nicotinate (0.28 g,0.78 mmol) in MeOH (3.9 mL) was added 1M NaOH (1.6 mL, 1.6 mmol). Themixture was heated at 100° C. for 5 minutes under microwave irradiation.Then the mixture was quenched with hydrochloric acid (1M) and extractedwith ethyl acetate. The organic layers were dried over MgSO₄, filteredand concentrated under reduced pressure to give the title compound.

Intermediate 24 2-chloro-6-methylnicotinamide

A mixture of (COCl)₂ (3.8 mL, 44 mmol) and 2-chloro-6-methylnicotinicacid (5.0 g, 29 mmol) in DCM (30 mL) was stirred at 20° C. for 2 hours.Then the mixture was concentrated under reduced pressure to give aresidue that was treated with THF (30 mL) and NH₃—H₂O (30 mL) at 20° C.for 2 hours. The resulting mixture was filtered and the filtrate wasconcentrated under reduced pressure to give the title compound.

Intermediate 25 2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

To a solution of 2-chloro-6-methylnicotinamide (3.0 g, crude) in NMP (50mL) were added DIPEA (2.3 g, 18 mmol) and 4,4-difluoropiperidinehydrochloride (2.8 g, 18 mmol). The mixture was stirred at 160° C. for 3hours, then diluted with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to a residue that was purified bysilica gel chromatography (0-25% EtOAc/petroleum ether) to give thetitle compound.

Intermediate 26N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

Step 1: 5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

To a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(1.3 g, 5.1 mmol) in DMF (20 mL) was added 1-bromopyrrolidine-2,5-dione(1.1 g, 6.1 mmol). The mixture was stirred at 11° C. for 2 hours, thendiluted with water and extracted with EtOAc. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue which was purified by silica gel chromatography (0-22%EtOAc/petroleum ether) to give the title compound.

Step 2:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

To a solution of5-bromo-2-(4,4-difluoro-piperidin-1-yl)-6-methylnicotinamide (200 mg,0.37 mmol) in 1,4-dioxane (4 mL) were added4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (150 mg, 0.45mmol), Xantphos-Pd-G2 (33 mg, 0.037 mmol) and Cs₂CO₃ (365 mg, 1.1 mmol)under an inert atmosphere in a glove box. The mixture was stirred at100° C. for 12 hours, then diluted with water and extracted with EtOAc.The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue that was purified by silica gelchromatography (PE/EtOAc=3:1) to give the title compound.

Intermediate 276-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide

Step 1: 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinonitrile

To a mixture of 2,6-dichloro-4-methylnicotinonitrile (50 mg, 0.27 mmol)in DMF (1 mL) was added K₂CO₃ (0.11 g, 0.80 mmol) and4,4-difluoropiperidine hydrochloride (46 mg, 0.29 mmol) under nitrogen.The mixture was stirred at 10° C. for 1 h, then at 90° C. for 16 h. Thenthe mixture was dissolved in water and extracted with EtOAc. The organiclayer was separated, washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (PE/ethyl acetate=10/1) togive the title compound.

Step 2: 6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide

To a mixture of6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinonitrile (0.42 g,1.6 mmol) in DMSO (4 mL) was added K₂CO₃ (0.65 g, 4.7 mmol) undernitrogen. The mixture was stirred at 0° C. for 1 h, then hydrogenperoxide (0.53 g, 7.8 mmol) was added. The mixture was stirred at 15° C.for 16 h, then dissolved in water and extracted with EtOAc. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (0-30% ethyl acetate/petroleum ethergradient) to give the title compound.

Intermediate 28 2,6-dichloronicotinamide

To a mixture of 2,6-dichloronicotinic acid (10 g, 52 mmol) and (COCl)₂(6.8 mL, 78 mmol) in dichloromethane (20 mL) was added DMF (0.040 mL,0.52 mmol). The mixture was stirred at 20° C. for 2 h, then concentratedunder reduced pressure. The resulting residue was dissolved in THF (20mL) and NH₃—H₂O (30 mL), and the mixture was stirred at 20° C. for 2 h.The mixture was filtered and the filtrate was concentrated under reducedpressure to give the title compound.

Intermediate 29 6-chloro-2-(4,4-difluoropiperidin-1-yl)nicotinamide

A mixture of DIPEA (1.5 mL, 8.8 mmol), 4,4-difluoropiperidinehydrochloride (0.55 g, 3.5 mmol) and 2,6-dichloronicotinamide (0.56 g,2.9 mmol) in NMP (10 mL) was stirred at 130° C. for 10 h. Then themixture was quenched with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue that was purified by flashsilica gel chromatography (0-26% ethyl acetate/PE) to give the titlecompound.

Intermediate 306-chloro-2-(4,4-difluoropiperidin-1-yl)-5-iodonicotinamide

To a stirred solution of6-chloro-2-(4,4-difluoropiperidin-1-yl)nicotinamide (0.30 g, 1.1 mmol)in acetonitrile (8.0 mL) was added NIS (0.73 g, 3.3 mmol) at 15° C. Themixture was stirred at 45° C. for 12 h. Then the mixture was dilutedwith EtOAc, washed with Na₂SO₃ aqueous solution, brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by silica gelchromatography (33% ethyl acetate/petroleum ether) to give the titlecompound.

Intermediate 31 methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate

Step 1: methyl 2,6-dichloronicotinate

To a solution of 2,6-dichloronicotinic acid (5.0 g, 26 mmol) in DCM (50mL) and MeOH (50 mL) was added (diazomethyl)trimethyl silane (39 mL, 78mmol). The mixture was stirred at 25° C. for 13 h, then diluted withwater and extracted with DCM. The organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (0-6% EtOAc/petroleum ether) togive the title compound.

Step 2: methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate

To a solution of methyl 2,6-dichloronicotinate (1.8 g, 8.7 mmol) in THF(15 mL) and DMF (15 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.3g, 17 mmol) and 4,4-difluoroazepane hydrochloride (1.5 g, 8.7 mmol). Themixture was stirred at 70° C. for 11 h, then diluted with water andextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (0-15% EtOAc/petroleum ether) togive the title compound.

Intermediate 325-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

Step 1: methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate (0.30g, 0.98 mmol), Pd(dppf)Cl₂ (72 mg, 0.098 mmol), potassiumcyclopropyltrifluoroborate (0.36 g, 2.5 mmol) and K₂CO₃ (0.41 g, 2.9mmol) in dioxane (5 mL) and water (1 mL) was degassed and backfilledwith nitrogen three times. The mixture was heated to 100° C. for 12 h.Then the mixture was cooled to room temperature, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (PE:EtOAc=5:1) to give the title compound.

Step 2: methyl5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate

To a solution of methyl6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate (0.13 g, 0.42 mmol)in DMF (2.5 mL) was added NCS (0.11 g, 0.84 mmol). The mixture wasstirred at 20° C. for 1 h, then heated to 30° C. for 12 h. The mixturewas quenched with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (ethyl acetate/PE=1/1, v/v) to give thetitle compound.

Step 3: 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid

A mixture of lithium hydroxide hydrate (79 mg, 1.9 mmol) and methyl5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate (0.13 g,0.38 mmol) in methanol (2.5 mL) and water (1 mL) was stirred at 50° C.for 12 h. The mixture was quenched with HCl (1M, 10 mL) and concentratedunder reduced pressure to give the title compound.

Step 4: 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid (0.11g, 0.33 mmol) in DCM (5 mL) was added oxalyl dichloride (0.13 g, 1.0mmol). The mixture was stirred at 30° C. for 1 h. Then the mixture wasconcentrated under vacuum to give a residue that was dissolved in THF(2.0 mL) and treated with a solution of NH₃—H₂O (0.5 mL) in THF (5.0 mL)at 30° C. The reaction mixture was stirred at 30° C. for 1 h, thenwashed with water and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue which was purified by silicagel chromatography (PE:EtOAc=2:1) to give the title compound.

Intermediate 332,5-dichloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: methyl 2,5-dichloro-6-cyclobutylnicotinate

To a mixture of sulfuric acid (0.78 mL, 15 mmol) andcyclobutanecarboxylic acid (2.8 mL, 29 mmol) in water (10 mL) was addedmethyl 2,5-dichloronicotinate (3.0 g, 15 mmol) followed by(nitrooxy)silver (0.74 g, 4.4 mmol). Then a solution of (NH₄)₂S₂O₈ (6.6g, 29 mmol) in water (10 mL) was added. The reaction mixture was stirredat 20° C. for 13 h, then extracted with EtOAc, dried over Na₂SO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound.

Step 2: 2,5-dichloro-6-cyclobutylnicotinic acid

A mixture of methyl 2,5-dichloro-6-cyclobutylnicotinate (2.2 g, 8.5mmol) and lithium hydroxide hydrate (1.4 g, 34 mmol) in MeOH (9 mL) andwater (3 mL) was stirred at 20° C. for 3 h. Then the mixture wasconcentrated under reduced pressure. The resulting residue dissolved inwater, acidified with 1N HCl to pH˜3, and extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to give the title compound.

Step 3: tert-butyltert-butyl((4-(2,5-dichloro-6-cyclobutylnicotinamido)pyridin-2-yl)sulfonyl)-carbamate

To a mixture of 2,5-dichloro-6-cyclobutylnicotinic acid (1.6 g crude)and tert-butyl ((4-aminopyridin-2-yl)sulfonyl)(tert-butyl)carbamate (2.1g, 6.5 mmol) in pyridine (8 mL) at 0° C. was added dropwise POCl₃ (1.2mL, 13 mmol). The mixture was stirred at 0° C. for 15 minutes, thenquenched with water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound.

Step 4:2,5-dichloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

A mixture of tert-butyltert-butyl((4-(2,5-dichloro-6-cyclobutylnicotinamido)pyridin-2-yl)sulfonyl)carbamate(2.5 g crude) and TFA (3 mL) in dichloromethane (9 mL) was stirred at20° C. for 2 h. Then the mixture was concentrated under reduced pressureto give a residue that was purified by silica gel chromatography(petroleum ether:ethyl acetate=1:1) to give the title compound.

Intermediate 342-chloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2-chloro-6-cyclobutylnicotinonitrile

To a solution of 2-chloronicotinonitrile (6.0 g, 43 mmol) andcyclobutanecarboxylic acid (8.7 g, 87 mmol) in water (20 mL) was addedAgNO₃ (2.2 g, 13 mmol) and (NH₄)₂S₂O₈ (20 g, 87 mmol). The mixture wasstirred at 20° C. for 60 minutes, then diluted with water and extractedwith EtOAc. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (0-5% ethyl acetate/petroleumether) to give the title compound.

Step 2: 2-chloro-6-cyclobutylnicotinamide

To a mixture of 2-chloro-6-cyclobutylnicotinonitrile (0.60 g, 3.1 mmol)in DMSO (2 mL) was added K₂CO₃ (0.86 g, 6.2 mmol), followed by H₂O₂(0.55 mL, 6.2 mmol). The mixture was stirred at 20° C. for 1 hour, thendiluted with water and extracted with EtOAc. The organic phase waswashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to give a residue that was purified by silica gelchromatography (petroleum ether/EtOAc=3:1) to give the title compound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-6-cyclobutylnicotinamide

To a solution of 2-chloro-6-cyclobutylnicotinamide (0.40 g, 1.9 mmol) indioxane (20 mL) was added Cs₂CO₃ (1.9 g, 5.7 mmol),4-bromo-N,N-bis(2,4-dimethoxy-benzyl)pyridine-2-sulfonamide (1.1 g, 2.1mmol) and XantPhos Pd G2 (0.17 g, 0.19 mmol). The mixture was degassedand backfilled with nitrogen three times, then stirred at 20° C. for 13h. The mixture was then diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (0-25% ethyl acetate/petroleum ether) to give thetitle compound.

Step 4: 2-chloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-6-cyclobutylnicotinamide(0.67 g, 1.0 mmol) in dichloromethane (5 mL) was added TFA (5 mL). Themixture was stirred at 20° C. for 2 h. Then the mixture was concentratedunder reduce pressure to give the title compound.

Intermediate 35 methyl6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of nickel(II) iodide (61 mg, 0.20 mmol),pyridine-2,6-bis(carboximidamide) (32 mg, 0.20 mmol) and zinc (0.26 g,3.9 mmol) were charged in a vial and the vial was evacuated andbackfilled with nitrogen. DMA (4 mL) was added and the mixture wasstirred for 5 minutes at 25° C.

A solution of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate(0.30 g, 0.98 mmol), bromocyclobutane (0.27 g, 2.0 mmol) and sodiumiodide (0.30 g, 2.0 mmol) in DMA (4 mL) was added to the mixture. Themixture was heated to 100° C. for 13 h. Then the mixture was filteredand the filtrate was diluted with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (PE:EtOAc=5:1) togive the title compound.

Intermediate 36 methyl5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate

Step 1: methyl 2-chloro-6-(trifluoromethyl)nicotinate

To a solution of 2-chloro-6-(trifluoromethyl)nicotinic acid (0.50 g, 2.2mmol) in DCM (10 mL) and MeOH (1.1 mL) at 25° C. under an atmosphere ofnitrogen was added dropwise (trimethylsilyl)diazomethane (1.8 mL, 3.6mmol; 2 M in diethyether). The mixture was stirred at 25° C. for 1 h.Then the mixture was quenched with AcOH (76 μl, 1.3 mmol), andconcentrated under reduced pressure. The resulting residue was dissolvedin EtOAc. The organic layer was separated, washed with water, saturatedNaHCO₃, dried over MgSO₄, filtered and concentrated to give a residuethat was purified by silica gel chromatography (0-30% ethylacetate:ethanol (3:1)/hexanes) to give the title compound.

Step 2: methyl2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate

To a solution of methyl 2-chloro-6-(trifluoromethyl)nicotinate (0.28 g,1.2 mmol) in N-methyl-2-pyrrolidinone (12 mL) was added4,4-difluoropiperidine (0.15 mL, 1.3 mmol) and K₂CO₃ (0.32 g, 2.3 mmol).The mixture was stirred at 60° C. for 4 h, then cooled to rt, dilutedwith water and extracted with EtOAc. The organic phase was washed withwater, dried over MgSO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (0-30% ethyl acetate:ethanol (3:1)/hexanes) to give thetitle compound.

Step 3: methyl5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate

To a solution of methyl2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate (0.10 g,0.31 mmol) in acetonitrile (1.5 mL) at 25° C. was added NBS (66 mg, 0.37mmol). The mixture was stirred at 25° C. for 2 h, then quenched withwater and extracted with EtOAc. The organic layer was separated, washedwith saturated NaHCO₃, dried over MgSO₄, filtered and concentrated togive a residue that was purified by silica gel chromatography (0-20%ethyl acetate/hexanes) to give the title compound.

Intermediate 372-chloro-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

Step 1: tert-butyltert-butyl((4-(2-chloro-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of 2-chloro-6-(trifluoromethyl)nicotinic acid (1.0 g, 4.4mmol) and tert-butyl (4-aminopyridin-2-yl)sulfonyl (tert-butyl)carbamate(1.5 g, 4.4 mmol) in pyridine (10 mL) was added POCl₃ (1.2 mL, 13 mmol).The mixture was stirred at 0° C. 10 min, then quenched with water andextracted with EtOAc. The organic layer was separated, washed withsaturated brine, dried over by Na₂SO₄, filtered and concentrated to givea residue that was purified by silica gel chromatography (0-30%petroleum ether/ethyl acetate) to give the title compound.

Step 2:2-chloro-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

To a mixture of tert-butyltert-butyl((4-(2-chloro-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)-carbamate(1.0 g, 1.9 mmol) in dichloromethane (16 mL) was added TFA (8.0 mL, 104mmol). The mixture was stirred at 20° C. for 1 h, then concentratedunder reduced pressure to give the title compound.

Intermediate 381-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane

A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (3.0 g, 14 mmol),DIPEA (7.3 mL, 42 mmol) and 4,4-difluoroazepane hydrochloride (2.9 g, 17mmol) in DMF (10 mL) was stirred at 20° C. for 10 h. Then the mixturewas diluted with water and extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (0-25% ethyl acetate/PE) to give the title compound.

Intermediate 39 tert-butyl((4-(5-bromo-2-(4,4-difluoropiperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)(tert-butyl)carbamate

Step 1: 5-bromo-2-(4,4-difluoropiperidin-1-yl)pyridine-3-carboxylic acid

To a mixture of 5-bromo-2-chloropyridine-3-carboxylic acid (8.0 g, 34mmol) in NMP (80 mL) was added DIPEA (14 g, 0.11 mol) and4,4-difluoropiperidine (4.5 g, 37 mmol) under nitrogen. The mixture wasstirred at 120° C. for 16 hours, then cooled to 0° C., quenched with 6MHCl and extracted with EtOAc. The organic layer was separated, washedwith brine and dried under reduced pressure to give a residue that wasrecrystallized from hexane to give the title compound.

Step 2: tert-butylN-([4-[5-bromo-2-(4,4-difluoropiperidin-1-yl)pyridine-3-amido]pyridin-2-yl]sulfonyl)-N-tert-butylcarbamate

To a solution of5-bromo-2-(4,4-difluoropiperidin-1-yl)pyridine-3-carboxylic acid (9.0 g,28 mmol) and tert-butyl (4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (9.2 g, 28 mmol) in pyridine (90 mL) was addedPOCl₃ (3.0 g, 20 mmol) at 0° C. The mixture was stirred at roomtemperature for 2 hours. Then the mixture was cooled to 0° C., quenchedwith water and extracted with EtOAc. The organic layer was separated,washed with saturated brine, and dried under reduced pressure to give aresidue that was purified by silica gel chromatography (33% ethylacetate/hexane) to give the title compound.

Intermediate 40 4,4-difluoroazepane Hydrochloride

Step 1: tert-butyl 4,4-difluoroazepane-1-carboxylate

To a solution of tert-butyl 4-oxoazepane-1-carboxylate (80 g, 0.38 mol)in DCM (0.56 L) at 0° C. was added dropwise a solution ofdiethylamino-sulfur trifluoride (240 g, 1.5 mol) in DCM (1.4 L). Themixture was stirred at 0° C. for 3.5 hours, then quenched into aqueoussodium hydrogen carbonate (saturated) and extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (6-50% EtOAc/hexanes) to givethe title compound.

Step 2: 4,4-dichloroazepane Hydrochloride

A mixture of tert-butyl 4,4-difluoroazepane-1-carboxylate (105 g, 1.0mol) and 4M HCl in dioxane (1.0 L, 4.0 mol) was stirred at roomtemperature for 1 hour. Then the mixture was concentrated under reducedpressure to give the title compound.

Intermediate 412,5-dichloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2,5-dichloro-4,6-dimethylnicotinamide

To a mixture of 2,5-dichloro-4,6-dimethylnicotinonitrile (1.0 g, 5.0mmol) and K₂CO₃ (1.4 g, 10 mmol) in DMSO (10 mL) was added H₂O₂ (0.87mL, 10 mmol). The mixture was stirred at 20° C. for 2 h. Then themixture was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (petroleum ether/ethyl acetate 1:2) to give the titlecompound.

Step 2: tert-butyltert-butyl((4-(2,5-dichloro-4,6-dimethylnicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of 2,5-dichloro-4,6-dimethylnicotinamide (1.0 g, 4.6 mmol)in 1,4-dioxane (15 mL) was added Cs₂CO₃ (3.0 g, 9.1 mmol),XantPhos-Pd-G2 (0.41 g, 0.46 mmol) and tert-butyl((4-bromopyridin-2-yl)sulfonyl)(tert-butyl)carbamate (Intermediate 7,2.0 g, 5.0 mmol). The reaction mixture was degassed and backfilled withnitrogen three times, then stirred at 100° C. for 13 h. The mixture wasdiluted with water, and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give the title compound which was used in the next stepwithout further purification.

Step 3:2,5-dichloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

A solution of tert-butyltert-butyl((4-(2,5-dichloro-4,6-dimethylnicotinamido)pyridin-2-yl)sulfonyl)carbamate(1.9 g crude) in DCM (10 mL) and TFA (20 mL) was stirred at 20° C. for 2h. The reaction mixture was concentrated under reduced pressure. Theresulting residue was diluted with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (petroleumether/ethyl acetate 1:2) give the title compound.

EXAMPLES Example 12-(4,4-difluoropiperidin-1-yl)-N-(6-sulfamoylpyrazin-2-yl)-5-(trifluoromethyl)nicotinamide

Step 1:N-(6-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyrazin-2-yl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-(4,4-difluoropiperidin-1l-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 20, 50 mg, 0.16 mmol) in 1,4-dioxane (1.5 mL) were addedCs₂CO₃ (110 mg, 0.32 mmol),6-chloro-N,N-bis(2,4-dimethoxybenzyl)pyrazine-2-sulfonamide (120 mg,0.243 mmol) and Brettphos-Pd-G3 (22 mg, 0.024 mmol). The mixture wasstirred at 100° C. for 13 hours, then filtered, diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give a residuewhich was purified by silica gel chromatography (PE/EtOAc=2:1) to givethe title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-N-(6-sulfamoylpyrazin-2-yl)-5-(trifluoromethyl)-nicotinamide

To a solution ofN-(6-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyrazin-2-yl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide(60 mg, 0.078 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixturewas stirred at 28° C. for 2 hours. Then the mixture was concentratedunder reduced pressure to give a residue that was purified by reversephase chromatography (45-100% MeCN/water with 0.1% TFA, C18 column) togive the title compound. LRMS m/z (M+H): calculated 467.1, observed466.9. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 9.71 (s, 1H), 8.90 (s, 1H), 8.59(d, J=1.2 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H), 3.67-3.70 (m, 4H), 2.04-2.13(m, 4H).

Example 22-(4,4-difluoropiperidin-1-yl)-N-(4-hydroxypyrimidin-2-yl)-5-(trifluoromethyl)nicotinamide

Step 1:2-(4,4-difluoropiperidin-1-yl)-N-(4-methoxypyrimidin-2-yl)-5-(trifluoromethyl)-nicotinamide

To a solution of 2-chloro-4-methoxypyrimidine (40 mg, 0.28 mmol) indioxane (3 mL) were added Cs₂CO₃ (0.27 g, 0.83 mmol),2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)-nicotinamide(Intermediate 20, 94 mg, 0.30 mmol) and Brettphos Pd G3 (50 mg, 0.055mmol). The mixture was stirred at 100° C. for 16 h under nitrogen. Thenthe mixture was purified by silica gel chromatography (petroleumether:EtOAc=3:1) to give the title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-N-(4-hydroxypyrimidin-2-yl)-5-(trifluoromethyl)-nicotinamide

To a solution of2-(4,4-difluoropiperidin-1-yl)-N-(4-methoxypyrimidin-2-yl)-5-(trifluoromethyl)nicotinamide(60 mg, 0.14 mmol) in acetonitrile (1 mL) were added sodium iodide (86mg, 0.57 mmol) and TMS-Cl (62 mg, 0.57 mmol) at 25° C. After 5 min, themixture was heated at 50° C. for 3 hours. Then the mixture was purifiedby reverse phase chromatography to give the title compound. LRMS m/z(M+H): calculated 404.1, observed 404.2. ¹H NMR δ (ppm) (400 MHz,CDCl₃): 8.71 (s, 1H), 8.45 (s, 1H), 7.75 (d, J=7.2 Hz, 1H), 6.31 (d,J=7.2 Hz, 1H), 3.52-3.60 (m, 4H), 2.15-2.29 (m, 4H).

Example 35-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinicacid

Brettphos Pd G3 (18 mg, 0.019 mmol) was added to a stirred mixture of2-(4,4-difluoro-piperidin-1-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 20, 40 mg, 0.13 mmol), Cs₂CO₃ (130 mg, 0.39 mmol), andmethyl 5-bromopicolinate (33 mg, 0.15 mmol) in 1, 4-dioxane (2 mL). Themixture was stirred at 100° C. for 18 h, then cooled to rt, treated withwater and extracted with ethyl acetate. The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue that was purified by reverse phase chromatography(40-100% AcCN/water with 0.1% TFA, C18 column) to give the titlecompound. LRMS m/z (M+H): calculated 431.1, observed 431.2. ¹H NMR δ(ppm) (400 MHz, CD₃OD): 9.10 (s, 1H), 8.56 (s, 1H), 8.49 (d, J=8.4 Hz,1H), 8.28 (d, J=8.3 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 3.59-3.84 (m, 4H),1.84-2.23 (m, 4H).

Example 44-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinicacid

Brettphos Pd G3 (8.8 mg, 9.7 μmol) was added to a stirred mixture of2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 20, 20 mg, 0.065 mmol), Cs₂CO₃ (63 mg, 0.19 mmol), andmethyl 4-bromopicolinate (17 mg, 0.078 mmol) in 1, 4-dioxane (2 mL). Themixture was stirred at 100° C. for 18 h, then cooled to rt, treated withwater and extracted with ethyl acetate. The combined organic layers weredried over Na₂SO₄, filtered and concentrated to give a residue that waspurified by reverse phase chromatography (40-100% AcCN/water with 0.1%TFA, C18 column) to give the title compound. LRMS m/z (M+H): calculated431.1, observed 431.2. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.64 (d, J=6.1Hz, 1H), 8.60 (s, 2H), 8.31-8.37 (m, 1H), 8.18 (d, J=2.2 Hz, 1H),3.63-3.75 (m, 4H), 1.96-2.15 (m, 4H).

Example 5N-(6-cyanopyridin-3-yl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 20, 20 mg, 0.065 mmol) in 1, 4-dioxane (2 mL) were addedCs₂CO₃ (63 mg, 0.19 mmol), 5-bromo-picolinonitrile (12 mg, 0.065 mmol)and Brettphos Pd G3 (8.8 mg, 9.7 μmol) with stirring at 25° C. Thereaction mixture was stirred at 100° C. for 12 h, then cooled to rt,treated with water and extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to givea residue that was purified by reverse phase chromatography (AcCN/waterwith 0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 412.1, observed 412.0. ¹H NMR δ (ppm) (400 MHz, CDCl₃): 10.23(s, 1H), 8.80 (d, J=1.6 Hz, 1H), 8.69 (s, 1H), 8.63 (dd, J=8.8, 2.2 Hz,1H), 8.49 (d, J=1.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 6.30 (s, 2H),3.51-3.67 (m, 4H), 2.09-2.28 (m, 4H).

Example 62-(azepan-1-yl)-N-(5-(methylsulfonyl)pyridin-3-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 18, 30 mg, 0.10 mmol) in dioxane (1.5 mL) was added Cs₂CO₃(68 mg, 0.21 mmol), 3-bromo-5-(methyl-sulfonyl)pyridine (25 mg) andBrettphos-Pd-G3 (9.5 mg, 10 μmol). The mixture was stirred at 100° C.for 13 hours. Then the mixture was filtered, diluted with DMF (3 mL),and purified by reverse phase chromatography (40-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 443.1, observed 443.0. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 9.07(d, J=2.4 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 8.46(d, J=1.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 3.60-3.67 (m, 4H), 3.24 (s,3H), 1.85 (br s, 4H), 1.55 (br s, 4H).

Example 72-(3-(hydroxymethyl)piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1:2-(3-(hydroxymethyl)piperidin-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-chloro-5-(trifluoromethyl)nicotinamide (Intermediate19, 60 mg, 0.27 mmol) in DMA (1.0 mL) was added piperidin-3-ylmethanol(31 mg, 0.27 mmol) and DIPEA (0.14 mL, 0.80 mmol) dropwise with stirringat 25° C. The reaction mixture was stirred at 100° C. for 12 h, thentreated with water and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate 1:2) to give the titlecompound.

Step 2: tert-butyltert-butyl((4-(2-(3-(hydroxymethyl)piperidin-1-yl)-5-(trifluoromethyl)-nicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of2-(3-(hydroxymethyl)piperidin-1-yl)-5-(trifluoromethyl)nicotinamide (20mg, 0.066 mmol) in 1,4-dioxane (1.0 mL) were added tert-butyltert-butyl((4-chloropyridin-2-yl)sulfonyl)carbamate (23 mg, 0.066 mmol),cesium carbonate (21 mg, 0.066 mmol) and Brettphos Pd G3 (60 mg, 0.066mmol) at 25° C. The reaction mixture was stirred at 100° C. for 12 hunder a nitrogen atmosphere. The mixture was then treated with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound.

Step 3:2-(3-(hydroxymethyl)piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide

To a solution of tert-butyltert-butyl((4-(2-(3-(hydroxymethyl)piperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(20 mg, 0.032 mmol) in DCM (2.0 mL) was added TFA (1.0 mL) dropwise withstirring at 25° C. The reaction mixture was stirred at 25° C. for 3 h.Then the mixture was concentrated under reduced pressure and purified byreversed phase chromatography (MeCN in water with 0.1% TFA, C18 column)to give the title compound. LRMS m/z (M+H): calculated 460.1; observed460.2. ¹H NMR δ (ppm) (400 MHz, CDCl₃): 10.77 (s, 1H), 8.56 (s, 1H),8.54 (s, 1H), 8.40-8.44 (m, 1H), 8.02 (s, 1H), 7.98-7.99 (m, 1H), 5.10(s, 2H), 3.63-3.66 (m, 2H), 3.56-3.57 (m, 2H), 2.91-2.98 (m, 2H),1.84-1.88 (m, 2H), 1.15-1.21 (m, 2H), 0.76-0.77 (m, 1H).

Example 82-(azepan-1-yl)-N-(5-carbamoylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide

Step 1:2-(azepan-1-yl)-N-(5-cyanopyridin-3-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 18, 45 mg, 0.16 mmol) in 1,4-dioxane (1.5 mL) were addedCs₂CO₃ (100 mg, 0.31 mmol), 5-bromonicotinonitrile (29 mg, 0.16 mmol)and Brettphos-Pd-G3 (14 mg, 0.016 mmol). The reaction was stirred at100° C. for 13 hours, then diluted with water and extracted with EtOAc.The combined organic layers was washed with brine, dried over Na₂SO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (petroleum ether/EtOAc=3:1) to give the titlecompound.

Step 2:2-(azepan-1-yl)-N-(5-carbamoylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-(azepan-1-yl)-N-(5-cyanopyridin-3-yl)-5-(trifluoromethyl)nicotinamide(42 mg, 0.11 mmol) in DMSO (3.0 mL) was added K₂CO₃ (30 mg, 0.22 mmol).The mixture was stirred at 20° C. for 20 min, then warmed to 30° C. andhydrogen peroxide (1.0 mL, 0.11 mmol) was added dropwise. The mixturewas stirred at 30° C. for 60 min. Then the mixture was filtered, treatedwith saturated Na₂SO₃ solution (1 mL), filtered, diluted with DMF (3 mL)and purified by reverse phase chromatography (30-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 408.2, observed 408.0. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 9.16(d, J=2.4 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.46(d, J=1.6 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 3.58-3.69 (m, 4H), 1.84 (brs, 4H), 1.54-1.56 (m, 4H).

Example 92-(4,4-difluoro-1-piperidyl)-6-methyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide

Step 1:N-(5-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-3-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

A mixture of Cs₂CO₃ (0.19 g, 0.59 mmol), Brettphos Pd G3 (18 mg, 0.020mmol), 5-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-3-sulfonamide (0.13g, 0.24 mmol), 2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(Intermediate 25, 50 mg, 0.20 mmol) and dioxane (2 ml) at 20° C. wassparged with a stream of nitrogen for 2 min. The tube was sealed andheated to 100° C. for 10 h. Then the mixture was cooled to rt, quenchedwith water and extracted with EtOAc. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (ethyl acetate/PE=1/1) to give the title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(5-sulfamoylpyridin-3-yl)nicotinamide(9)

To a solution ofN-(5-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-3-yl)-2-(4,4-difluoro-piperidin-1-yl)-6-methylnicotinamide(50 mg, 0.070 mmol) in DCM (6 ml) was added TFA (0.027 ml, 0.35 mmol).The mixture was stirred at 20° C. for 2 h. Then the mixture was filteredand the filtrate was concentrated under reduced pressure to give aresidue that was purified by reverse phase chromatography (30-100% MeCNin water with 0.1% TFA, C18 column) to give the title compound. LRMS m/z(M+H): calculated 412.1, observed 412.1. ¹H NMR δ (ppm) (400 MHz,CD₃OD): 8.95 (br s, 1H), 8.82 (br d, J=10.96 Hz, 2H), 8.32 (d, J=2.63Hz, 1H), 7.97 (d, J=2.63 Hz, 1H), 3.52 (br t, J=5.48 Hz, 4H), 1.98-2.11(m, 4H).

TABLE 1 The compounds of Exmple 10 was prepared according to a syntheticprocedure similar to the synthetic procedure for Example 9. Calc'dObserved Example Compound Name [M + H]⁺ [M + H]⁺ 10

5-chloro-2-(4,4-difluoro-1- piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3- carboxamide 432.1 431.9

Example 116-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(5-sulfamoylpyridin-3-yl)nicotinamide

Step 1:N-(5-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-3-yl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide

A mixture of tBu-Xphos Pd G3 (11 mg, 0.014 mmol),6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide(Intermediate 27, 40 mg, 0.14 mmol), sodium 2-methylpropan-2-olate (26mg, 0.28 mmol),5-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-3-sulfonamide (0.11 g, 0.21mmol), and THF (2.5 mL) at 20° C. was sparged with a stream of nitrogenfor 1 min, then sealed and heated to 60° C. for 12 h. The mixture wasquenched with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (petroleum ether:EtOAc=1:1) to give the title compound.

Step 2:6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(5-sulfamoylpyridin-3-yl)-nicotinamide

To a stirred solution ofN-(5-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-pyridin-3-yl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide(50 mg, 0.067 mmol) in DCM (2 mL) was added TFA (1.0 mL, 13 mmol). Themixture was stirred at 20° C. for 1 h. Then the mixture was concentratedunder reduced pressure to give a residue that was purified by reversephase chromatography (35-100% MeCN in water with 0.1% TFA, C18 column)to give the title compound. LRMS m/z (M+H): calculated 446.1, observed446.2. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.76-8.95 (m, 3H), 6.90 (s, 1H),3.44-3.62 (m, 4H), 2.33 (s, 3H), 1.72-2.06 (m, 4H).

Example 125,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)nicotinamide

To a stirred solution of6-chloro-2-(4,4-difluoropiperidin-1-yl)-5-iodonicotinamide (Intermediate30, 0.20 g, 0.50 mmol) in toluene (5.0 mL) and water (0.8 mL) was addedpotassium carbonate (0.21 g, 1.5 mmol), potassiumcyclopropyltrifluoroborate (0.30 g, 2.0 mmol), Pd(PPh₃)₄ (80 mg, 0.069mmol) at 15° C. under a nitrogen atmosphere. The mixture was stirred at120° C. for 12 h, then cooled to room temperature and diluted withEtOAc. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure to givea residue that was purified by silica gel chromatography (petroleumether/EtOAc=1:1) to give the title compound.

Step 2:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)nicotinamide

A mixture of5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)nicotinamide (50 mg,0.16 mmol), 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide(125 mg, 0.23 mmol), sodium tert-butoxide (45 mg, 0.47 mmol), andtBuXphos-Pd-G3 (30 mg, 0.038 mmol) in THF (2 mL) was degassed andbackfilled with nitrogen three times. The mixture was heated to 60° C.for 12 h, then diluted with EtOAc. The organic phase was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (petroleum ether/EtOAc=2:1) to give the title compound.

Step 3:5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide

A mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)nicotinamide(50 mg, 0.064 mmol) in CH₂Cl₂ (2 mL) and TFA (0.5 mL) was stirred at 20°C. for 4 h. Then the solvent was removed under reduced pressure to givea residue that was purified by silica gel chromatography(CH₂Cl₂/CH₃OH=20:1) to give the title compound. LRMS m/z (M+H):calculated 478.2, observed 478.1. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56(d, J=6.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.6, 2.0 Hz, 1H),7.65 (s, 1H), 3.34-3.39 (m, 4H), 2.51-2.70 (m, 1H), 1.96-2.10 (m, 5H),0.99-1.13 (m, 6H), 0.59-0.69 (m, 2H).

Example 132-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1: 2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-chloro-5-(trifluoromethyl)nicotinamide (Intermediate19, 0.50 g, 2.2 mmol) in DMA (1 mL) was added 4,4-difluoroazepanehydrochloride (0.57 g, 3.3 mmol) and DIPEA (1.2 mL, 6.7 mmol) at 25° C.The mixture was stirred at 120° C. for 12 h, then diluted with EtOAc andwashed with water. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (55%EtOAc/petroleum ether) to give the title compound.

Step 2:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamide

A mixture of tBuXphos Pd G3 (49 mg, 0.062 mmol),2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamide (200 mg,0.62 mmol), sodium 2-methylpropan-2-olate (120 mg, 1.2 mmol),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (400 mg, 0.74mmol) and THF (2.5 mL) was sealed in a tube within a glove box under aninert atmosphere and heated to 60° C. for 12 h. Then the reactionmixture was quenched with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (petroleum ether in EtOAc) to give the titlecompound.

Step 3:2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamide(280 mg, 0.36 mmol) in DCM (2 mL) was added TFA (1.0 mL, 13 mmol) andstirred at 20° C. for 1 h. The mixture was then concentrated underreduced pressure to give a residue that was purified by reverse phasechromatography (33-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 480.1, observed 480.2. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.57 (d, J=5.6 Hz, 1H), 8.51 (s, 1H), 8.39(d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.88 (dd, J=2.0, 5.2 Hz, 1H),3.76-3.86 (m, 2H), 3.47 (s, 2H), 2.26-2.43 (m, 2H), 1.88-2.01 (m, 4H).

Example 145-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(Intermediate 26, 50 mg, 0.063 mmol) in toluene (2 mL) and water (0.4mL) were added potassium cyclopropyltrifluoroborate (47 mg, 0.32 mmol),Pd(dppf)Cl₂ (9.2 mg, 0.013 mmol) and K₂CO₃ (18 mg, 0.13 mmol) and themixture was degassed with nitrogen. The mixture was then stirred at 100°C. for 12 hours, diluted with water and extracted with EtOAc. Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound.

Step 2:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(40 mg, 0.053 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixturewas stirred at 11° C. for 2 hours. Then the mixture was filtered andpurified by reverse phase chromatography (30-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 452.1, observed 452.1. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.59(d, J=5.6 Hz, 1H), 8.42 (s, 1H), 7.85-7.87 (m, 1H), 7.76 (s, 1H),3.46-3.48 (m, 4H), 2.66 (s, 3H), 2.04-2.13 (m, 4H), 1.88-1.96 (m, 1H),1.01-1.04 (m, 2H), 0.68-0.71 (m, 2H).

Example 155-cyclobutyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1:5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(Intermediate 26, 90 mg, 0.11 mmol) in DCM (3 mL) was added TFA (0.6mL). The reaction mixture was stirred at 10° C. for 2 hours, thendiluted with water and extracted with EtOAc. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue that was purified by silica gel chromatography (petroleumether/EtOAc=1:1) to give the title compound.

Step 2:5-cyclobutyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a vial was added nickel(II) iodide (7.6 mg, 0.024 mmol),pyridine-2,6-bis(carboximidamide) (4.0 mg, 0.024 mmol) and zinc (32 mg,0.49 mmol) and the vial was evacuated and backfilled with N₂. Then DMA(0.5 mL) was added and the mixture was stirred for 5 minutes at 12° C.

A solution of5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide(60 mg, 0.12 mmol), bromocyclobutane (33 mg, 0.24 mmol) and sodiumiodide (37 mg, 0.24 mmol) in DMA (0.3 mL) was added to the vial. Themixture was stirred at 100° C. for 12 hours, then diluted with water andextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by reverse phase chromatography (30-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 466.2, observed 466.1. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.58(d, J=4.8 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 7.88 (d, J=6.4 Hz, 1H),7.85-7.87 (m, 1H), 3.62-3.68 (m, 1H), 3.40-3.43 (m, 4H), 2.43 (s, 3H),2.39-2.41 (m, 2H), 2.05-2.11 (m, 7H), 1.89-1.91 (m, 1H).

Example 165-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

A solution ofN-(2-(N,N-bis(2,4-dimethoxy-benzyl)sulfamoyl)pyridin-4-yl)-5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(Intermediate 26, 80 mg, 0.10 mmol) in DMF (1 mL) under an atmosphere ofnitrogen was added to a mixture of ethynylcyclopropane (6.7 mg, 0.10mmol), copper(I) iodide (19 mg, 0.10 mmol), Pd(PPh₃)₂Cl₂ (7.1 mg, 10μmol) and triethylamine (100 mg, 1.0 mmol). The mixture was heated to100° C. for 13 hours, then diluted with water and extracted with EtOAc.The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated to give a residue that was purified by silica gelchromatography (petroleum ether/EtOAc=1:1) to give the title compound.

Step 2:5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(70 mg, 0.050 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixturewas stirred at 18° C. for 2 hours. Then the mixture was filtered andconcentrated to give a residue that was purified by reverse phasechromatography (30-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 476.1, observed 476.0. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.57 (d, J=5.6 Hz, 1H), 8.42 (d, J=2.0 Hz,1H), 7.84-7.86 (m, 1H), 7.80 (s, 1H), 3.49-3.52 (m, 4H), 2.53 (s, 3H),1.97-2.06 (m, 4H), 1.51-1.53 (m, 1H), 0.90-0.92 (m, 2H), 0.74-0.77 (m,2H).

Example 172-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide

To a stirred mixture of 2-chloro-6-methylnicotinamide (Intermediate 24,0.50 g, 2.9 mmol) and 4,4-difluoroazepane hydrochloride (0.60 g, 3.5mmol) was added DIPEA (1.5 mL, 8.8 mmol). The mixture was stirred at160° C. for 3 h. Then the mixture was cooled to rt, diluted in water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated under reducedpressure to give a residue, that was purified by flash silica gelchromatography (0-60% ethyl acetate/petroleum ether) to give the titlecompound.

Step 2: tert-butyltert-butyl((4-(2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)pyridin-2-yl)sulfonyl)carbamate

A mixture of t-Bu Xphos-Pd-G3 (0.12 g, 0.15 mmol), sodium2-methylpropan-2-olate (0.29 g, 3.0 mmol),2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (0.40 g, 1.5 mmol),tert-butyl (4-bromopyridin-2-yl)sulfonyl(tert-butyl)carbamate (0.62 g,1.8 mmol) under an atmosphere of nitrogen was suspended in THF (15 mL).The mixture was stirred at 80° C. for 10 h, then cooled to rt, dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure to give a residue, that was purified by silica gelchromatography (petroleum ether:EtOAc=3:1) to give the title compound.

Step 3:2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a stirred mixture of tert-butyltert-butyl((4-(2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamido)-pyridin-2-yl)sulfonyl)carbamate(0.45, 0.77 mmol, 16-1b) in DCM (5 mL) was added TFA (2.5 mL, 32 mmol)dropwise at room temperature. The mixture was stirred at rt for 1 h.Then the mixture was concentrated under reduced pressure to give aresidue, that was purified by reverse phase chromatography (18-100% MeCNin water with 0.1% TFA, C18 column) to give the title compound. LRMS m/z(M+H): calculated 426.1, observed 426.2. ¹H NMR δ (ppm) (400 MHz,CD₃OD): 8.56 (d, J=6.4 Hz, 1H), 8.38 (s, 1H), 7.84-7.88 (m, 2H), 6.78(d, J=8.0 Hz, 1H), 3.72-3.74 (m, 2H), 3.49-3.51 (m, 2H), 2.50 (s, 3H),2.34-2.40 (m, 2H), 1.93-2.01 (m, 4H).

Example 186-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of 2,6-dichloronicotinamide (Intermediate 28, 1.0 g, 5.2mmol) in NMP (10 mL) were added 4,4-difluoroazepane hydrochloride (0.99g, 5.8 mmol) and DIPEA (2.7 mL, 16 mmol). The mixture was stirred at130° C. for 3 hours, then diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (15% EtOAc) to give the titlecompound.

Step 2: 6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinamide (0.10g, 0.34 mmol) in toluene (1.5 mL) was added Cs₂CO₃ (0.34 g, 1.0 mmol),potassium cyclopropylmethyltrifluoroborate (84 mg, 0.52 mmol) andDTBPF-Pd-G3 (61 mg, 0.069 mmol). The mixture was stirred at 100° C. for10 hours under an atmosphere of nitrogen. Then the mixture was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated to givea residue that was purified by silica gel chromatography (petroleumether/ethyl acetate=1/2) to give the title compound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide (15 mg,0.048 mmol) in dioxane (1.5 mL) was added Cs₂CO₃ (47 mg, 0.14 mmol),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (39 mg, 0.073mmol) and Xantphos-Pd-G2 (4.3 mg, 4.8 μmol). The reaction mixture wasdegassed and backfilled with nitrogen three times. The mixture wasstirred at 100° C. for 13 h, then diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound.

Step 5:6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(18)

A solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide(25 mg, crude) in dichloromethane (3 mL) and TFA (1 mL) was stirred at20° C. for 2 h. Then the mixture was concentrated under reduced pressureand purified by reverse phase chromatography (39-100% MeCN in water with0.1% 10 mM NH₄CO₃, C18 column) to give the title compound. LRMS m/z(M+H): calculated 466.2, observed 466.2. ¹H NMR δ (ppm) (400 MHz,CD₃OD): 8.56 (d, J=5.6 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.85-7.87 (m,1H), 7.83 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 3.70-3.79 (m, 2H),3.47 (t, J=6.0 Hz, 2H), 2.63 (d, J=7.2 Hz, 2H), 2.32-2.41 (m, 2H),1.88-2.08 (m, 4H), 1.04-1.19 (m, 1H), 0.47-0.61 (m, 2H), 0.18-0.31 (m,2H).

Example 192-(4,4-difluoroazepan-1-yl)-5,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2-chloro-5,6-dimethylnicotinoyl chloride

2-hydroxy-5,6-dimethylnicotinic acid (1.0 g, 6.0 mmol) was added toPOCl₃ (5.0 mL, 54 mmol) slowly. The mixture was stirred for 30 min at20° C., and stirred at 100° C. for 10 hours. Then the mixture wasconcentrated under reduced pressure to give the title compound.

Step 2: 2-chloro-5,6-dimethylnicotinamide

To a solution of 2-chloro-5,6-dimethylnicotinoyl chloride (1.2 g, 5.9mmol) in dichloromethane (5 mL) was added NH₃—H₂O (5.0 mL, 36 mmol). Themixture was stirred at 20° C. for 1 h, then diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the titlecompound.

Step 3: 2-(4,4-difluoroazepan-1-yl)-5,6-dimethylnicotinamide

To a solution of 2-chloro-5,6-dimethylnicotinamide (0.40 g, 2.2 mmol) inNMP (5 mL) were added 4,4-difluoroazepane hydrochloride (0.56 g, 3.2mmol) and DIPEA (1.1 mL, 6.5 mmol). The mixture was stirred at 200° C.for 0.5 hours under microwave irradiation. Then the mixture was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (dichloromethane/MeOH=20/1) to give the title compound.

Step 4:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5,6-dimethylnicotinamide

To a solution of 2-(4,4-difluoroazepan-1-yl)-5,6-dimethylnicotinamide(0.26 g, 0.92 mmol) in dioxane (4 mL) were added Cs₂CO₃ (0.90 g, 2.7mmol), XantPhos Pd G2 (82 mg, 0.092 mmol) and4-bromo-N,N-bis(2,4-dimethoxybenzyl)-pyridine-2-sulfonamide (0.59 g, 1.1mmol). The mixture was degassed and backfilled with nitrogen threetimes. Then the mixture was stirred at 100° C. for 13 h, andconcentrated under reduced pressure to give the title compound.

Step 5:2-(4,4-difluoroazepan-1-yl)-5,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5,6-dimethylnicotinamide(0.65 g crude) in dichloromethane (3 mL) was added TFA (3 mL). Themixture was stirred at 20° C. for 2 h. The mixture was concentratedunder reduced pressure and purified by reverse phase chromatography(23-100% MeCN in water with 0.1% TFA, C18 column) to give the titlecompound. LRMS m/z (M+H): calculated 440.2, observed 440.2. ¹H NMR δ(ppm) (400 MHz, CD₃OD): 8.54 (d, J=5.6 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H),7.83-7.85 (m, 1H), 7.55 (s, 1H), 3.62-3.70 (m, 2H), 3.34-3.41 (m, 2H),2.40 (s, 3H), 2.27-2.39 (m, 2H), 2.22 (s, 3H), 1.81-2.07 (m, 4H).

Example 205-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide

Step 1:6-chloro-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)nicotinamide

To a stirred solution of6-chloro-2-(4,4-difluoropiperidin-1-yl)-5-iodonicotinamide (Intermediate30, 0.70 g, 1.7 mmol) in toluene (10 mL) and water (1.0 mL) were addedpotassium cyclopropyltrifluoroborate (0.52 g, 3.5 mmol), potassiumcarbonate (0.72 g, 5.2 mmol) and Pd(PPh₃)₄ (0.20 g, 0.17 mmol) under anitrogen atmosphere. The mixture was stirred at 110° C. for 12 h, thencooled to room temperature and diluted with EtOAc. The organic layer waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether/ethyl acetate=1:1) to givethe title compound.

Step 2:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide

To a stirred solution of 2,2,2-trifluoroethanol (0.32 g, 3.2 mmol) inDMF (3 mL) was added Cs₂CO₃ (0.62 g, 1.9 mmol) at 0° C. The mixture wasstirred at 0° C. for 10 min, then6-chloro-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)nicotinamide (0.20g, 0.63 mmol) was added. The reaction was stirred at 100° C. for 12 h.Then the mixture was cooled to room temperature, filtered and thefiltrate was purified by reverse phase chromatography (53-100% MeCN inwater with 0.1% TFA, C18 column) to give the title compound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide

A mixture of5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide(50 mg, 0.13 mmol),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (78 mg, 0.14mmol), Cs₂CO₃ (0.13 g, 0.39 mmol), and XantPhos Pd G2 (12 mg, 0.014mmol) in dioxane (1.2 mL) was degassed and backfilled with nitrogenthree times. The mixture was heated to 100° C. for 12 h, then cooled toroom temperature and diluted with EtOAc. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound.

Step 4:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide(20)

To a stirred solution ofN-(2-(N,N-bis(2,4-dimethoxy-benzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide(110 mg crude) in dichloromethane (2 mL) was added TFA (0.5 mL). Themixture was stirred at 20° C. for 2 h. Then the mixture was concentratedunder reduced pressure to give a residue that was purified by reversephase chromatography (55-100% MeCN in water with 0.1% TFA, C18 column)to give the title compound. LRMS m/z (M+H): calculated 536.1, observed536.2. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56 (d, J=5.6 Hz, 1H), 8.42 (d,J=1.6 Hz, 1H), 7.84 (dd, J=5.6, 1.6 Hz, 1H), 7.60 (s, 1H), 4.95 (q,J=8.8 Hz, 2H), 3.44 (t, J=5.6 Hz, 4H), 1.86-2.20 (m, 5H), 0.89-0.97 (m,2H), 0.64-0.73 (m, 2H).

Example 215-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

A mixture of5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide(Intermediate 32, 12 mg, 0.036 mmol),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (29 mg, 0.055mmol), Cs₂CO₃ (36 mg, 0.11 mmol), Ruphos Pd G3 (6.1 mg, 7.3 μmol) anddioxane (1.5 mL) was degassed and backfilled with nitrogen three times.The mixture was stirred at 70° C. for 2.5 h, then diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (petroleum ether:EtOAc=2:1) to give the title compound.

Step 2:5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(21)

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide(15 mg, 0.019 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixturewas stirred at 20° C. for 20 min. Then the mixture was concentratedunder reduced pressure to give a residue that was purified by reversephase chromatography (43-100% MeCN in water with 0.1% TFA, C18 column)to give the title compound. LRMS m/z (M+H): calculated 486.1, observed486.0. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.55-8.58 (m, 1H), 8.39 (s, 1H),7.86-7.87 (m, 1H), 7.76 (s, 1H), 3.65-3.67 (m, 2H), 3.38-3.41 (m, 2H),2.31-2.52 (m, 1H), 2.28-2.32 (m, 2H), 1.91-1.97 (m, 4H), 1.06-1.10 (m,4H).

Example 226-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

A mixture of5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide(Intermediate 32, 12 mg, 0.036 mmol),4-bromo-N,N-bis(2,4-dimethoxy-benzyl)pyridine-2-sulfonamide (29 mg,0.055 mmol), Cs₂CO₃ (36 mg, 0.119 mmol), Ruphos Pd G3 (6.1 mg, 7.3 μmol)and dioxane (1.5 mL) was degassed and backfilled with nitrogen threetimes. The mixture was stirred at 70° C. for 2.5 h, then diluted withwater and extracted with EtOAc. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (petroleum ether:EtOAc=2:1) to give the title compound.

Step 2:6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide(20 mg, 0.027 mmol) in dichloromethane (2 mL) was added TFA (0.4 mL).The mixture was stirred at 25° C. for 1 h. Then the mixture wasconcentrated under reduced pressure to give a residue that was purifiedby reverse phase chromatography (37-100% MeCN in water with 0.1% TFA,C18 column) to give the title compound. LRMS m/z (M+K): calculated452.1, observed 452.2. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.53 (t, J=5.6Hz, 1H), 8.36 (s, 1H), 7.83-7.85 (m, 1H), 7.66 (d, J=8.0 Hz, 1H), 6.72(d, J=7.6 Hz, 1H), 3.63-3.66 (m, 2H), 3.36-3.39 (m, 2H), 2.23-2.33 (m,2H), 1.90-2.03 (m, 5H), 0.93-1.02 (m, 4H).

Example 235-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: methyl5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of NCS (0.11 g, 0.80 mmol) and methyl6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinate (Intermediate 35,0.13 g, 0.40 mmol) in DMF (2.5 mL) was stirred at 20° C. for 1 h, thenat 30° C. for 12 h. The mixture was then treated with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (ethyl acetate/petroleum ether=5/1, v/v) to give thetitle compound.

Step 2: 5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid

A mixture of lithium hydroxide hydrate (76 mg, 1.8 mmol) and methyl5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinate (130 mg,0.36 mmol) in MeOH (2.5 mL) and water (1 mL) was stirred at 50° C. for12 h. Then the reaction mixture was quenched with HCl (1M, 10 mL) andconcentrated under reduced pressure to give the title compound.

Step 3: 5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1l-yl)nicotinic acid (0.11 gcrude) in DCM (5 mL) was added oxalyl dichloride (0.12 g, 0.96 mmol).The mixture was stirred at 30° C. for 1 h. Then the mixture wasconcentrated at reduced pressure to give a residue that was treated witha solution of NH₃*H₂O (0.5 mL) in THF (5 mL). The reaction mixture wasstirred at 30° C. for 1 h, then diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (PE:EtOAc=1:1) togive the title compound.

Step 4:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

A mixture of5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide (50 mg,0.14 mmol), 4-bromo-N,N-bis(2,4-dimethoxy-benzyl)pyridine-2-sulfonamide(0.12 g, 0.22 mmol), Cs₂CO₃ (0.14 g, 0.44 mmol), Ruphos Pd G3 (24 mg,0.029 mmol) and dioxane (3 mL) was degassed and backfilled with nitrogenthree times. The mixture was stirred at 70° C. for 3 h, then dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether:EtOAc=2:1) to give thetitle compound.

Step 5:5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(23)

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide(0.13 g, 0.071 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixturewas stirred at 20° C. for 1 h. The mixture was then concentrated underreduced pressure to give a residue that was purified by reverse phasechromatography (30-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 500.1, observed 500.0. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.53 (t, J=5.6 Hz, 1H), 8.38 (s, 1H),7.84-7.86 (m, 1H), 7.72 (s, 1H), 3.91-3.99 (m, 1H), 3.75-3.78 (m, 2H),3.40-3.43 (m, 2H), 2.29-2.43 (m, 6H), 1.87-2.13 (m, 6H).

Example 246-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid

A mixture of lithium hydroxide hydrate (32 mg, 0.77 mmol) and methyl6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinate (Intermediate 35, 50mg, 0.15 mmol) in methanol (2.5 mL) and water (1 mL) was stirred at 50°C. for 12 h. Then the mixture was quenched with HCl (1M, 10 mL) andconcentrated under reduced pressure to give the title compound.

Step 2: 6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of 6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid(45 mg, crude) in DCM (5 mL) was added oxalyl dichloride (55 mg, 0.43mmol). The mixture was stirred at 30° C. for 1 h. The mixture wasconcentrated under reduced pressure to give a residue that was dissolvedin THF (2 mL) and treated with a solution of NH₃*H₂O (0.5 mL) in THF (3mL). The mixture was stirred at 30° C. for 1 h. The mixture was dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (PE:EtOAc=2:1) to give the title compound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

A mixture of 6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide (30mg, 0.097 mmol), Cs₂CO₃ (95 mg, 0.29 mmol),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (78 mg, 0.14mmol), Ruphos Pd G3 (16 mg, 0.019 mmol) and dioxane (3 mL) was degassedand backfilled with nitrogen three times. The mixture was stirred at 70°C. for 3 h, then diluted with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (petroleumether:EtOAc=2:1) to give the title compound.

Step 4:6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(24)

A mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)nicotinamide(60 mg, 0.078 mmol) in DCM (2 mL) and TFA (0.4 mL) was stirred at 25° C.for 1 h. Then the mixture was concentrated under reduced pressure togive a residue that was purified by reverse phase chromatography(23-100% MeCN in water with 0.1% TFA, C18 column) to give the titlecompound. LRMS m/z (M+H): calculated 466.2, observed 466.0. ¹H NMR δ(ppm) (400 MHz, CD₃OD): 8.53 (t, J=5.6 Hz, 1H), 8.36 (s, 1H), 7.83-7.85(m, 1H), 7.76 (d, J=7.6 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 3.75-3.77 (m,2H), 3.58-3.60 (m, 1H), 3.44-3.36 (m, 2H), 2.30-2.39 (m, 6H), 1.93-1.97(m, 6H).

Example 252-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1: Ethyl 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate

To a stirred solution of ethyl 2-chloro-5-cyano-6-methylnicotinate (0.50g, 2.2 mmol), and 4,4-difluoroazepane (0.45 g, 3.3 mmol) in NMP (15 mL)was added N-ethyl-N-isopropylpropan-2-amine (0.86 g, 6.7 mmol). Themixture was stirred at 70° C. for 2 hours, then cooled to roomtemperature, treated with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (EtOAc in hexane) to give the title compound.

Step 2: 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid

To a stirred solution of ethyl5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinate (0.70 g, 2.2mmol) and ethanol (8.7 mL) was added 1N NaOH (2.2 mL, 2.2 mmol). Themixture was stirred at 55° C. for 4 hours. Then the mixture wasacidified with 0.1 N HCl and extracted with EtOAc. The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound.

Step 3: 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide

To a solution of oxalyl chloride (1.9 mL, 3.8 mmol) and5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinic acid (0.75 g, 2.5mmol) in DCM (6.4 mL) was added a drop of DMF. The mixture was heated atreflux for 1 hour. Then the mixture was concentrated under reducedpressure to give a residue that was dissolved in THF (6.4 mL) andtreated with ammonium hydroxide (1.8 mL, 13 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 1 hour, then diluted with water andextracted with ethyl acetate. The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give thetitle compound.

Step 4:5-cyano-2-(4,4-difluoroazepan-1-yl)-N-(2-(N-(2,4-dimethoxybenzyl)-N-(2,5-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-methylnicotinamide

A mixture of 5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide(0.60 g, 2.0 mmol),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (1.3 g, 2.4mmol), Xantphos Pd G3 (0.48 g, 0.51 mmol) and cesium carbonate (1.3 g,4.1 mmol) in dioxane (2.0 mL) was sparged with nitrogen for 2 minutes.The mixture was heated at 100° C. in a sealed tube for 24 hours. Thenthe mixture was diluted with EtOAc, washed with water, brine, dried overMgSO₄ and concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (EtOAc in hexane) to give thetitle compound.

Step 5:5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a stirred solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyano-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide(0.60 g, 0.80 mmol) in CH₂Cl₂ (4 mL) was added TFA (3.1 mL, 40 mmol).The mixture was stirred for 4 hours, and then quenched with MeOH. Theresulting mixture was stirred for 5 minutes, then filtered to remove thesolids. The filtrate was concentrated under reduced pressure and theresulting residue was dissolved in EtOAc. The organic layer was washedwith saturated NaHCO₃, brine, dried over MgSO₄ and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (EtOAc in hexane) to give the title compound. LRMS m/z(M+H): calculated 451.1, observed 451.2. ¹H NMR δ (ppm) (500 MHz,DMSO-d₆): 11.11 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 8.27 (s, 1H), 8.20 (s,1H), 7.82 (d, J=5.7 Hz, 1H), 7.45 (s, 2H), 3.70 (m, 2H), 3.42 (d, J=5.8Hz, 2H), 3.32 (m, 2H), 2.55 (s, 3H), 2.32 (m, 2H), 2.08-1.80 (m, 2H).

Example 262-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: Methyl 2-(4,4-difluoropiperidin-1-yl)nicotinate

A suspension of methyl 2-fluoro-nicotinate (0.12 g, 0.77 mmol) andpotassium carbonate (0.13 g, 0.93 mmol) in N-methyl-2-pyrrolidinone (3.9mL) was treated with 4,4-difluoropiperidine (0.096 mL, 0.85 mmol). Themixture was stirred at 60° C. for 18 h. Then the mixture was cooled tort, diluted with water and extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (0-30% ethyl acetate:ethanol (3:1)/hexanes) to give thetitle compound.

Step 2: 2-(4,4-difluoropiperidin-1-yl)nicotinic acid

To a solution of methyl 2-(4,4-difluoropiperidin-1-yl)nicotinate (0.18g, 0.71 mmol) in THF (2.8 mL) and MeOH (0.71 mL) was added aqueous LiOH(0.85 mL, 0.85 mmol, 1 M). The mixture was stirred at 50° C. for 3 h.Then the mixture was concentrated under reduced pressure to give aresidue that was suspended in water, acidified with 1 N HCl andextracted with EtOAc. The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure to give the titlecompound.

Step 3: tert-butyltert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of 2-(4,4-difluoropiperidin-1-yl)nicotinic acid (0.075 g,0.31 mmol) and tert-butyl(4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (0.10 g, 0.31 mmol)in pyridine (1.5 mL) at 0° C. was added POCl₃ (32 μl, 0.34 mmol)dropwise via a syringe and the mixture stirred at 0° C. for 1 h. Thenthe reaction mixture was slowly quenched with brine and extracted withEtOAc. The combined organic layers were washed with water, brine, driedover MgSO₄, filtered and concentrated under reduced pressure to afford aresidue that was purified by silica gel chromatography (0-30% ethylacetate:ethanol (3:1)/hexanes) to give the title compound.

Step 4:2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(26)

A solution of tert-butyltert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)-carbamate,(65 mg, 0.12 mmol) in DCM (1.2 mL) was treated with TFA (0.45 mL, 5.9mmol) and the mixture was stirred at 25° C. for 3 h. Then the mixturewas concentrated under reduced pressure. The resulting residue wassuspended in saturated NaHCO₃ and extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (0-25% ethyl acetate:ethanol (3:1)/hexanes) to give thetitle compound. LRMS m/z (M+H): calculated 398.1, observed 398.1. ¹H NMRδ (ppm) (500 MHz, CD₃OD): 8.59 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 8.35(dd, J=4.9, 1.9 Hz, 1H), 7.98 (dd, J=7.5, 1.8 Hz, 1H), 7.86 (dd, J=5.5,2.0 Hz, 1H), 7.06 (dd, J=7.5, 4.9 Hz, 1H), 3.52-3.46 (m, 4H), 2.05 (m,4H).

Example 275-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide

Step 1: methyl 6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)nicotinate(Intermediate 31, 0.30 g, 0.98 mmol), Pd(dppf)Cl₂ (72 mg, 0.098 mmol),potassium cyclopropyltrifluoroborate (0.36 g, 2.5 mmol) and K₂CO₃ (0.41g, 2.9 mmol) in dioxane (5 mL) and water (1 mL) was evacuated andbackfilled with nitrogen three times. The mixture was heated to 100° C.for 12 h. Then the mixture was filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (petroleum ether:EtOAc=5:1) to give the title compound.

Step 2: methyl5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of NCS (0.11 g, 0.84 mmol) and methyl6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate (0.13 g, 0.42 mmol)in DMF (2.5 mL) was stirred at 20° C. for 1 h, then heated at 30° C. for12 h. Then the mixture was diluted with water and extracted with EtOAc.The organic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (ethyl acetate/PE=1/1) to givethe title compound.

Step 3: 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid

A mixture of methyl5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinate (0.20 g,0.58 mmol) and LiOH—H₂O (0.15 g, 3.5 mmol) in MeOH (6 mL) and water (0.2mL) was stirred at 60° C. for 12 h. Then the mixture was treated withHCl/MeOH to pH˜6, and concentrated under reduced pressure to give thetitle compound.

Step 4: 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide

To a solution of5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinic acid (0.14g, 0.42 mmol) in dichloromethane (5 mL) was added oxalyl dichloride(0.11 mL, 1.3 mmol). The mixture was stirred at 30° C. for 1 h, and thenconcentrated under reduced pressure. The resulting residue was dissolvedin THF (2 mL) and treated with a solution of NH₃—H₂O (0.5 mL) in THF(5.0 mL) at 30° C. The mixture was stirred at 30° C. for 1 h, thendiluted with water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by reverse phasechromatography (42-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound.

Step 5:5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)nicotinamide

A mixture of5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)nicotinamide (50 mgcrude), t-BuONa (0.23 mL, 0.45 mmol), 4-chloro-2-methoxypyridine (35 mg,0.24 mmol) and t-BuXPhos Pd G3 (10 mg, 0.015 mmol) in THF (10 mL) wasdegassed and backfilled with nitrogen three times. The mixture washeated to 60° C. for 12 h, then diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (ethyl acetate/petroleumether=1/5) to give the title compound.

Step 6:5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide(27)

A mixture of5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-methoxypyridin-4-yl)nicotinamide(60 mg, 0.14 mmol), KI (35 mg, 0.21 mmol), MeCN (1 mL) and TMSCl (0.053mL, 0.41 mmol) was heated to 70° C. for 1 h. Then the mixture wasconcentrated under reduced pressure to give a residue that was purifiedby reverse phase chromatography (37-100% MeCN in water with 0.1% TFA,C18 column) to give the title compound. LRMS m/z (M+H): calculated423.1, observed 422.9. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 7.71 (s, 1H),7.59 (d, J=7.2 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 6.87-6.93 (m, 1H),3.58-3.67 (m, 2H), 3.35 (t, J=6.0 Hz, 2H), 2.43-2.53 (m, 1H), 2.19-2.35(m, 2H), 1.84-2.02 (m, 4H), 0.98-1.11 (m, 4H).

Example 282-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1: Methyl2-(5,5-difluoro-2-oxoazepan-1-yl)-5-(trifluoromethyl)nicotinate

To a suspension of 5,5-difluoro-2-azepanone (0.11 g, 0.71 mmol) in DMF(3.5 mL) was added NaH (43 mg, 1.1 mmol) at room temperature. Themixture was stirred for 10 min, then methyl2-chloro-5-(trifluoromethyl)nicotinate (0.17 g, 0.71 mmol) was added.The mixture was stirred 16 h, then quenched with hydrochloric acid (1M)and extracted with ethyl acetate. The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (0-100%EtOAc/hexanes) to give the title compound.

Step 2: 2-(5,5-Difluoro-2-oxoazepan-1-yl)-5-(trifluoromethyl)nicotinicacid

To a solution of methyl2-(5,5-difluoro-2-oxoazepan-1-yl)-5-(trifluoromethyl)nicotinate (49 mg,0.14 mmol) in THF (350 μl) and water (350 μl) was added lithiumhydroxide monohydrate (12 mg, 0.28 mmol). The mixture was stirred at rtfor 1 hour, then quenched with hydrochloric acid (1M) and extracted withethyl acetate. The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure to give the titlecompound.

Step 3: tert-Butyltert-butyl((4-(2-(5,5-difluoro-2-oxoazepan-1-yl)-5-(trifluoromethyl)-nicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of2-(5,5-difluoro-2-oxoazepan-1-yl)-5-(trifluoromethyl)nicotinic acid (44mg, 0.13 mmol) and tert-butyl(4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (43 mg, 0.13 mmol) inpyridine (650 μl) at 0° C. was added POCl₃ (13 μl, 0.14 mmol). Themixture was stirred 0° C. for 1 hour, then quenched with brine andextracted with ethyl acetate. The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (0-100%EtOAc/hexanes) to give the title compound.

Step 4:2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide

To a solution of tert-butyltert-butyl((4-(2-(5,5-difluoro-2-oxoazepan-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(40 mg, 0.062 mmol) in DCM (0.3 mL) was added TFA (0.31 mL). The mixturewas stirred at room temperature for 2 hours. Then the mixture wasquenched with aqueous sodium hydrogen carbonate (saturated) andextracted with dichloromethane. The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (0-100%EtOAc/hexanes) to give the title compound. LRMS m/z (M+H): calculated494.1, observed 494.1. ¹H NMR δ (ppm) (600 MHz, DMSO-d₆): 11.30 (s, 1H),9.02 (m, 1H), 8.57 (m, 1H), 8.44 (m, 1H), 8.19 (m, 1H), 7.78 (m, 1H),7.43 (s, 2H), 4.19 (m, 2H), 2.65 (m, 2H), 2.34 (m, 2H), 2.16 (m, 2H).

TABLE 2 The compounds of Exmples 29-42 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 28.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ 29

2-(4,4-Dichloropiperidin-1- yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)- nicotinamide 498.0 498.1 30

2-(4,4-difluoroazepan-1-yl)- N-[1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]- 5-(trifluoromethyl)pyridine- 3-carboxamide518.1 518.3 31

5-chloro-2-(4,4- difluoroazepan-1-yl)-6- methyl-N-[1-(methylsulfonyl)-1H- pyrazol-4-yl]pyridine-3- carboxamide 448.1 448.3 32

5-chloro-2-(4,4- difluoroazepan-1-yl)-4,6- dimethyl-N-[1-(methylsulfonyl)-1H- pyrazol-4-yl]pyridine-3- carboxamide 462.1 462.3 33

N-{1-[(2- aminoethyl)sulfonyl]-1H- pyrazol-4-yl}-5-chloro-2-(4,4-difluoroazepan-1-yl)-6- methylpyridine-3- carboxamide 477.1 477.434

2-(4,4-difluoroazepan-1-yl)- N-[1-(methylsulfonyl)-1H- indazol-3-yl]-5-(trifluoromethyl)pyridine-3- carboxamide 518.1 518.3 35

2-(4,4-difluoroazepan-1-yl)- N-[1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]- 5-(trifluoromethyl)pyridine- 3-carboxamide518.1 518.5 36

N-[1-(cyclopropylsulfonyl)- 1H-pyrazol-4-yl]-2-(4,4-difluoroazepan-1-yl)-5- (trifluoromethyl)pyridine-3- carboxamide 494.1494.3 37

N-[5-cyclopropyl-1- (methylsulfonyl)-1H- pyrazol-4-yl]-2-(4,4-difluoroazepan-1-yl)-5- (trifluoromethyl)pyridine-3- carboxamide 508.1508.4 38

2-cyclopropyl-4-(4,4- difluoroazepan-1-yl)-N-(2- sulfamoylpyridin-4-yl)pyrimidine-5- carboxamide 453.1 453.4 39

6-cyclopropyl-3-(4,4- difluoroazepan-1-yl)-N-(2- sulfamoylpyridin-4-yl)pyridazine-4- carboxamide 453.1 453.4 40

6-methyl-N-(2- sulfamoylpyridin-4-yl)-2- (3,4,4-trifluoroazepan-1-yl)nicotinamide 444.1 444.4 41

5-chloro-2-(4,4- difluoroazepan-1-yl)-6- methoxy-N-(2-sulfamoylpyridin-4- yl)pyridine-3-carboxamide 476.1 476.3 42

N-[2-(tert- butylsulfamoyl)pyridin-4- yl]-5-chloro-2-(4,4-difluoroazepan-1-yl)-6- methoxypyridine-3- carboxamide 532.1 532.4

Example 435-cyano-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

Step 1: methyl5-cyano-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate

In a glove box, a solution of methyl5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate(Intermediate 36, 96 mg, 0.24 mmol) in acetonitrile (1.6 mL) was treatedwith Xphos-Pd-G2 (19 mg, 0.024 mmol), dicyanozinc (42 mg, 0.37 mmol) andpotassium phosphate (30 μl, 0.36 mmol). The flask was sealed and thereaction mixture was stirred under nitrogen at 70° C. for 4 h. Then themixture was cooled to rt, diluted with EtOAc and filtered throughCelite™. The filtrate was concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography, (0-30% ethylacetate:ethanol (3:1)/hexanes) to give the title compound.

Step 2:5-cyano-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinic acid

A solution of methyl5-cyano-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate (82mg, 0.23 mmol) in THF (0.94 mL) and MeOH (0.24 mL) was treated with LiOH(0.24 mL, 0.24 mmol, 1.0 M in water). The mixture was stirred at 25° C.for 2 h. Then the mixture was concentrated and the resulting residue wasdissolved in water, acidified with 1N HCl and extracted with EtOAc. Theorganic layer was dried over MgSO₄, filtered and concentrated to givethe title compound.

Step 3: tert-butyltert-butyl((4-(5-cyano-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)-nicotinamido)pyridin-2-yl)sulfonyl)carbamate

A solution of5-cyano-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinic acid(77 mg, 0.23 mmol) and tert-butyl(4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (76 mg, 0.23 mmol) inpyridine (1.1 mL) at 0° C. was treated with POCl₃ (0.024 mL, 0.25 mmol)dropwise via a syringe. The mixture was stirred at 0° C. for 1.5 h. Thenthe mixture was quenched with saturated aqueous NaCl and extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-20% ethyl acetate/hexanes)to give the title compound.

Step4:5-cyano-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-nicotinamide

A solution of tert-butyltert-butyl((4-(5-cyano-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(50 mg, 0.077 mmol) in DCM (0.39 mL) was treated with TFA (0.30 mL, 3.9mmol). The mixture was stirred at 25° C. for 5 h. Then the mixture wasconcentrated under reduced pressure and the resulting residue wassuspended in NaHCO₃ and extracted with EtOAc. The organic layer wasdried over MgSO₄, filtered and concentrated under reduced pressure togive a residue that was purified by silica gel chromatography (0-30%ethyl acetate:ethanol (3:1)/hexanes) to give the title compound. LRMSm/z (M+H): calculated 491.1, observed 491.2. ¹H NMR δ (ppm) (500 MHz,DMSO-d₆): 11.35 (s, 1H), 8.65 (d, J=5.4 Hz, 1H), 8.56 (s, 1H), 8.28 (d,J=1.5 Hz, 1H), 7.86-7.81 (m, 1H), 7.49 (s, 2H), 3.73-3.67 (m, 4H),2.14-2.06 (m, 4H).

Example 445-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

Step 1: methyl5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)-nicotinate

In a glove box, to a vial containing methyl5-bromo-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinate(Intermediate 36, 62 mg, 0.15 mmol) and cyclopropylacetylene (52 μl,0.62 mmol) was added DMF (0.77 mL), followed by Pd(PPh₃)₄ (8.9 mg, 7.7μmol), copper(I) iodide (1.5 mg, 7.7 μmol), and TEA (86 μl, 0.62 mmol).The vial was sealed and heated at 40° C. for 24 h. Then the mixture wasdiluted with EtOAc and washed with water, followed by brine. The organiclayer was dried over MgSO₄, filtered and concentrated to give a residuethat was purified by silica gel chromatography (0-10% ethylacetate/hexanes) to give the title compound.

Step 2:5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinicacid

A solution of methyl5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)-nicotinate(45 mg, 0.12 mmol) in THF (0.46 mL) and MeOH (0.12 mL) was treated withLiOH (0.12 mL, 0.12 mmol, 1.0 M in water). The mixture was stirred at25° C. for 2 h, then concentrated under reduced pressure. The resultingresidue was diluted with water, acidified with 1N HCl and extracted withEtOAc. The organic layer was dried over MgSO₄, filtered and concentratedto give the title compound.

Step 3: tert-butyltert-butyl((4-(5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

A solution of5-(cyclopropyl-ethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinicacid (37 mg, 0.099 mmol) and tert-butyl(4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (33 mg, 0.099 mmol)in pyridine (0.49 mL) at 0° C. was treated with POCl₃ (10 μl, 0.11 mmol)dropwise via a syringe. The mixture was stirred at 0° C. for 1.5 h, thenquenched with brine and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure to give the title compound.

Step 4:5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

A solution of tert-butyltert-butyl((4-(5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(67 mg, 0.098 mmol) in DCM (0.49 mL) was treated with TFA (0.38 mL, 4.9mmol). The mixture was stirred at 25° C. for 5 h, then concentratedunder reduced pressure. The resulting residue diluted in NaHCO₃ andextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (0-30% ethyl acetate:ethanol(3:1)/hexanes) to give the title compound. LRMS m/z (M+H): calculated430.1, observed 430.3. ¹H NMR δ (ppm) (500 MHz, DMSO-d₆): 11.24 (s, 1H),8.63 (d, J=5.4 Hz, 1H), 8.30 (d, J=1.7 Hz, 1H), 8.05 (s, 1H), 7.82 (d,J=3.6 Hz, 1H), 7.48 (s, 2H), 3.58-3.52 (m, 4H), 3.41-3.36 (m, 1H), 2.01(d, J=18.2 Hz, 4H), 1.59 (td, J=8.1, 4.0 Hz, 1H), 0.97-0.89 (m, 2H),0.76-0.69 (m, 2H).

Example 452-(azepan-1-yl)-N-(3-cyano-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide

To a solution of 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinic acid(Intermediate 17, 20 mg, 0.069 mmol) in pyridine (1.0 mL) was addedphosphoryl trichloride (11 mg, 0.069 mmol). The mixture was stirred at20° C. for 5 min, then 5-amino-1,2,4-oxadiazole-3-carbonitrile (7.7 mg)was added and the resulting mixture was stirred at 50° C. for 2.5 h,then at 60° C. for 10 h. Then the mixture was cooled to rt, diluted withwater and extracted with EtOAc. The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by reverse phase chromatography (MeCN in water with 0.1%TFA, C18 column) to give the title compound. LRMS m/z (M+H): calculated381.1, observed 381.0. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.49 (s, 1H),8.08 (s, 1H), 3.53-3.55 (m, 4H), 1.85-1.86 (m, 4H), 1.54-1.55 (m, 4H).

Example 465-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: methyl 5-bromo-2-(4,4-difluoroazepan-1-yl)nicotinate

To a solution of methyl 5-bromo-2-chloronicotinate (0.60 g, 2.4 mmol) inDMA (10 mL) was added 4,4-difluoroazepane (0.65 g, 4.8 mmol) andN-ethyl-N-isopropylpropan-2-amine (1.2 g, 9.6 mmol). The mixture wasstirred at 100° C. for 2 h, then diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue that was purified by silica gel chromatography (30%EtOAc) to give the title compound.

Step 2: methyl5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of methyl 5-bromo-2-(4,4-difluoroazepan-1-yl)nicotinate (0.50g, 1.4 mmol), potassium (cyclopropyl-methyl)trifluoroborate (0.46 g, 2.9mmol), P(tBu)₃—Pd-G2 (73 mg, 0.14 mmol) and Cs₂CO₃ (1.4 g, 4.3 mmol) intoluene (5 mL) was degassed and backfilled with nitrogen three times.The mixture was heated to 100° C. for 12 h. Then the mixture was cooledto rt, washed with water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by reverse phasechromatography (39-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound.

Step 3: lithium5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinate

A mixture of methyl5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinate (75 mg, 0.23mmol) and LiOH—H₂O (29 mg, 0.69 mmol) in MeOH (1.5 mL) and water (0.8mL) was stirred at 45° C. for 13 h. Then the mixture was concentratedunder reduced pressure to give the title compound.

Step 4:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide

A mixture of 4-amino-N,N-bis(2,4-dimethoxy-benzyl)pyridine-2-sulfonamide(90 mg, 0.19 mmol), PyBOP (0.13 g, 0.25 mmol) and lithium5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinate (40 mgcrude) in DMF (4 mL) was stirred at 20° C. for 12 h. The reactionmixture was quenched with water and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether:EtOAc=1:1) to give thetitle compound.

Step 5:5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

A mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)nicotinamide(13 mg, 0.017 mmol) in dichloromethane (3 mL) and TFA (1 mL) was stirredat 20° C. for 0.5 h. Then the mixture was concentrated under reducedpressure to give a residue that was purified by by reverse phasechromatography (34-100% MeCN in water with 0.1% 10 mM NH₄CO₃, C18column) to give the title compound. LRMS m/z (M+H): calculated 466.2,observed 466.3. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56 (d, J=5.2 Hz, 1H),8.38 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.87 (d, J=5.6 Hz, 1H), 7.73 (d,J=1.6 Hz, 1H), 3.63-3.72 (m, 2H), 3.42 (t, J=6.0 Hz, 2H), 2.50 (d, J=7.2Hz, 2H), 2.32 (d, J=10.0 Hz, 2H), 1.87-2.05 (m, 4H), 0.98 (br s, 1H),0.49-0.57 (m, 2H), 0.23 (q, J=5.2 Hz, 2H).

Examples 47 and 48(S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(47) and(R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(48)

Step 1: (R andS)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-chloro-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 21, 75 mg, 0.20 mmol) in NMP (1 mL) were added4,4-difluoro-3-methylpiperdine hydrochloride (34 mg, 0.2 mmol) and DIPEA(0.10 mL, 0.59 mmol). The mixture was heated at 70° C. for 4 hours, thenquenched with aqueous potassium phosphate monobasic (saturated) andextracted with ethyl acetate. The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to give aresidue that was purified on silica gel (0-100% EtOAc/hexanes) to givethe title compound.

Step 2: (R orS)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(47) and (S orR)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(48)

(R andS)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide (77 mg, 0.16 mmol) was purified by preparative SFC (AD-H,25% EtOH/CO₂, 100 bar) to give the title compounds: enantiomer A (47)[(R orS)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;and enantiomer B (48) [(S orR)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide.Enantiomer A (47): LRMS m/z (M+H): calculated 480.1, observed 480.3, ¹HNMR δ (ppm) (600 MHz, DMSO-d₆): 11.21 (s, 1H), 8.59 (d, J=4.9 Hz, 2H),8.26 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.81 (d, J=3.7 Hz, 1H), 7.45 (s,2H), 3.86 (t, J=13.7 Hz, 2H), 3.26-3.19 (m, 1H), 3.11-2.93 (m, 1H), 2.11(m, 2H), 1.87 (m, 1H), 0.86 (d, J=6.8 Hz, 3H)]; Enantiomer B (48): LRMSm/z (M+H): calculated 480.1, observed 480.3, ¹H NMR δ (ppm) (600 MHz,DMSO-d₆): 11.20 (s, 1H), 8.59 (d, J=5.1 Hz, 2H), 8.25 (s, 1H), 8.13 (d,J=2.2 Hz, 1H), 7.90-7.72 (m, 1H), 7.44 (s, 2H), 3.96-3.75 (m, 2H), 3.23(t, J=10.9 Hz, 1H), 3.09-2.93 (m, 1H), 2.11 (s, 2H), 1.93 (s, 1H), 0.86(d, J=6.8 Hz, 3H).

TABLE 3 The compounds of Exmples 49-130 were prepared according to asynthetic procedure similar to the synthetic procedure for Examples 47and 48. Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺Conditions 49

(R or S)-2-(4,4-dichloro- 3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin- 4-yl)-5-(trifluoro- methyl)nicotinamide 512.1512.1 Chiral Method I, peak 1 50

(S or R)-2-(4,4-dichloro- 3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin- 4-yl)-5-(trifluoro- methyl)nicotinamide 512.1512.1 Chiral Method I, peak 2 51

2-(4,4-Dichloroazepan- 1-yl)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoro-methyl)nicotinamide 512.1 512.1 150° C. for 10 minutes in Step 3 52

2-[(3S,5R)-4,4-difluoro- 3,5-dimethyl-1- piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 494.1494.1 150° C. for 10 minutes in Step 3 53

5-chloro-2-[(3S,5R)-4,4- difluoro-3,5-dimethyl-1- piperidyl]-6-methyl-N-(2-sulfamoyl-4- pyridyl)pyridine-3- carboxamide 474.1 474.1 200° C. for10 minutes in Step 3 54

(S or R)-5-chloro-2-(4,4- difluoro-3- methylpiperidin-1-yl)-6-methyl-N-(2- sulfamoylpyridin-4- yl)nicotinamide 460.1 460.1 200° C. for90 minutes in Step 3, Chiral Method D, peak 2 55

(S or R)-5-chloro-2-(4,4- difluoro-3- methylpiperidin-1-yl)-6-methyl-N-(2- sulfamoylpyridin-4- yl)nicotinamide 460.1 460.1 200° C. for90 minutes in Step 3, Chiral Method D, peak 1 56

(S or R)-2-(3- methylpiperidin-1-yl)-N- (2-sulfamoylpyridin-4-yl)-5-(trifluoro- methyl)nicotinamide 444.1 444.1 100° C. for 10 minutesin Step 3; Chiral Method I, peak 2 57

(R or S)-2-(3- methylpiperidin-1-yl)-N- (2-sulfamoylpyridin-4-yl)-5-(trifluoro- methyl)nicotinamide 444.1 444.1 100° C. for 10 minutesin Step 3; Chiral Method I, peak 2 58

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2- [(1S,5S or 1R,5R)-1-(trifluoromethyl)-3- azabicyclo[3.2.0]heptan- 3-yl]pyridine-3-carboxamide 510.1 510.1 Chiral Method D, peak 2 59

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2- [(1R,5R or 1S,5S)-1-(trifluoromethyl)-3- azabicyclo[3.2.0]heptan- 3-yl]pyridine-3-carboxamide 510.1 510.1 Chiral Method D, peak 1 60

N-(2-sulfamoylpyridin- 4-yl)-2-((1R,5S)-6,6,7,7- tetrafluoro-3-azabicyclo[3.2.0]heptan- 3-yl)-5-(trifluoro- methyl)nicotinamide 514.1514.1 70° C. for 16 hours in Step 3 61

2-[(1S,6S or 1R,6R)-7,7- difluoro-6-methyl-3- azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4- pyridyl)-5-(trifluoro- methyl)pyridine-3-carboxamide 492.1 492.1 Chiral method A, peak 2 62

2-[(1R,6R or 1S,6S)-7,7- difluoro-6-methyl-3- azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4- pyridyl)-5-(trifluoro- methyl)pyridine-3-carboxamide 492.1 492.1 Chiral method A, peak 1 63

2-((1R,5S)-8,8-difluoro- 3-azabicyclo- [3.2.1]octan-3-yl)-N-(2-sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)- nicotinamide 492.1 492.1150° C. for 10 minutes in Step 3 64

2-((1R,5S or 1S.5R)-6,6- difluoro-3-azabicyclo-[3.2.0]heptan-3-yl)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-nicotinamide 478.1 478.1 Chiral Method D, peak 2 65

2-((1S,5R or 1R,5S)-6,6- difluoro-3-azabicyclo-[3.2.0]heptan-3-yl)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-nicotinamide 478.1 478.1 Chiral Method D, peak 1 66

(R or S)-2-(1,1-difluoro- 5-azaspiro[2.5]octan-5- yl)-N-(2-sulfamoyl-pyridin-4-yl)-5- (trifluoromethyl)nicotin- amide 492.1 492.1 ChiralMethod E, peak 1 67

(S or R)-2-(1,1-difluoro- 5-azaspiro[2.5]octan-5- yl)-N-(2-sulfamoyl-pyridin-4-yl)-5- (trifluoromethyl)nicotin- amide 492.1 492.1 ChiralMethod E, peak 2 68

2-((1R,5S)-3- azabicyclo[3.2.0]heptan- 3-yl)-N-(2-sulfamoyl-pyridin-4-yl)-5- (trifluoromethyl)nicotin- amide 442.1 442.1 70° C. for16 hours in Step 3 69

2-((1S,6S or 1R,6R)-7,7- difluoro-3- azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoyl- pyridin-4-yl)-5- (trifluoro- methyl)nicotinamide478.1 478.1 Chiral Method B, peak 1 70

2-((1R,6R or 1S,6S)-7,7- difluoro-3- azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoyl- pyridin-4-yl)-5- (trifluoro-methyl)- nicotinamide478.1 478.1 Chiral Method B, peak 2 71

2-[(1R,4R or 1S,4S)-5,5- difluoro-2- azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)pyridine-3-carboxamide 478.1 478.1 Chiral Method C, peak 1 72

2-[(1S,4S or 1R,4R)-5,5- difluoro-2- azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)pyridine-3-carboxamide 478.1 478.1 Chiral Method C, peak 2 73

(R or S)-2-(4,4-difluoro- 2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin- 4-yl)-5-(trifluoro- methyl)nicotinamide 480.1480.1 200° C. for 0.5 hour in Step 3; Chiral Method F peak 1 74

(S or R)-2-(4,4-difluoro- 2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin- 4-yl)-5-(trifluoro- methyl)nicotinamide 480.1480.1 200° C. for 0.5 hour in Step 3; Chiral Method F peak 2 75

2-((3R,4s,5S)-4- hydroxy-3,4,5- trimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin- 4-yl)-5-(trifluoro- methyl)nicotinamide 488.2488.2 70° C. for 16 hours in Step 3 76

2-((1R,5S)-6,6-difluoro- 3-azabicyclo- [3.1.1]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)- 5-(trifluoro- methyl)nicotinamide 478.1 478.170° C. for 16 hours in Step 3 77

2-[(3S,4S)-4-hydroxy-3- methyl-1-piperidyl]-N- (2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)- pyridine-3-carboxamide 460.1 460.1 70° C. for 16hours in Step 3 78

2-[(3S,4r,5R)-4- hydroxy-3,5-dimethyl-1- piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 474.1474.2 70° C. for 16 hours in Step 3 79

2-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5- yl)-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 484.1 484.2 80

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[3-(trifluoromethyl)-1- piperidyl]pyridine-3- carboxamide 498.1 498.2 81

2-[3-(3,5- difluorophenyl)-1- piperidyl]-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 542.1 542.3 82

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[4-(trifluoromethyl)-1- piperidyl]pyridine-3- carboxamide 498.1 498.2 83

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[3- [[4-(trifluoro-methyl)phenyl]methyl]- 1-piperidyl]pyridine-3- carboxamide 588.1 588.384

N-(2-sulfamoyl-4- pyridyl)-2- thiomorpholino-5- (trifluoromethyl)pyridine-3-carboxamide 448.1 448.2 85

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[3-[4-(trifluoromethyl)- phenyl]pyrrolidin-1- yl]pyridine-3- carboxamide560.1 560.2 86

2-(3-benzyl-6,8-dihydro- 5H-imidazo[1,2- a]pyrazin-7-yl)-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 558.2558.3 87

2-[3,3-dimethyl-4-(2,2,2- trifluoroethyl)piperazin-1-yl]-N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)pyridine-3-carboxamide 541.1 541.3 88

2-(2,2- dimethylmorpholin-4- yl)-N-(2-sulfamoyl-4- pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 460.1 460.2 89

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[8-(trifluoromethyl)-3,4- dihydro-1H-isoquinolin- 2-yl]pyridine-3-carboxamide 546.1 546.2 90

N-(2-sulfamoyl-4- pyridyl)-2-[4- (trifluoromethoxy)isoin-dolin-2-yl]-5-(trifluoro- methyl)pyridine-3- carboxamide 548.1 548.2 91

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[2-[4-(trifluoromethyl)- phenyl]morpholin-4- yl]pyridine-3- carboxamide576.1 576.2 92

N-(2-sulfamoyl-4- pyridyl)-2-(3,3,4,4- tetrafluoropyrrolidin-1-yl)-5-(trifluoro- methyl)pyridine-3- carboxamide 488.1 488.1 93

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[3-(trifluoromethyl)azetidin- 1-yl]pyridine-3- carboxamide 470.1 470.2 94

2-(3-pyrazol-1- ylpyrrolidin-1-yl)-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 482.1 482.2 95

2-[2-(4-fluorophenyl)-1- piperidyl]-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 524.1 524.2 96

2-(2,3,3a,5,6,6a- hexahydrofuro[3,2- b]pyrrol-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 458.1458.2 97

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[3-[4-(trifluoromethyl)- phenoxy]azetidin-1- yl]pyridine-3- carboxamide562.1 562.2 98

N-(2-sulfamoyl-4- pyridyl)-5- (trifluoromethyl)-2-[4-[3-(trifluoromethyl)- phenoxy]-1- piperidyl]pyridine-3- carboxamide590.1 590.3 99

2-[4- (cyclopropylmethyl)-3- oxo-piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)- 5-(trifluoromethyl)- pyridine-3-carboxamide499.1 499.2 100

N-(2-sulfamoyl-4- pyridyl)-2-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-5- (trifluoromethyl)- pyridine-3-carboxamide 513.1 513.2 101

5-chloro-2-(4,4- difluoroazepan-1-yl)-N- (2-sulfamoyl-4-pyridyl)pyridine-3- carboxamide 446.9 447.2 120° C. in Step 3 102

2-((2R,6S)-2-methyl-6- (trifluoromethyl)morpho- lino)-N-(2-sulfamoyl-pyridin-4-yl)-5- (trifluoromethyl)nicotin- amide 514.1 514.1 103

2-((2S,6R)-2-methyl-6- (trifluoromethyl)morpho- lino)-N-(2-sulfamoyl-pyridin-4-yl)-5- (trifluoromethyl)nicotin- amide 514.4 514.1 104

(S)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4- oxazepan-4- yl)nicotinamide 514.1 514.1 105

(R)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4- oxazepan-4- yl)nicotinamide 514.4 514.1 106

2-[(2R)-6,6-dimethyl-2- (trifluoromethyl)-1,4- oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 542.1542.2 107

2-(2,2-dimethyl-1,4- oxazepan-4-yl)-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 474.1 474.2 108

2-[(7S)-7-methyl-1,4- oxazepan-4-yl]-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 460.1 460.2 109

N-[2-(tert- butylsulfamoyl)-4- pyridyl]-5-chloro-2-(4,4-difluoroazepan-1- yl)pyridine-3- carboxamide 503.0 503.1 110

2-[(2S)-2- methylmorpholin-4-yl]- N-(2-sulfamoyl-4- pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 446.1 446.1 111

2-[(2R)-2-methyl-1,4- oxazepan-4-yl]-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 460.1 460.1 112

2-(3-hydroxy-3-methyl- 1-piperidyl)-N-(2- sulfamoyl-4-pyridyl)-5-(trifluoromethyl) pyridine-3-carboxamide 460.1 460.2 113

2-(6-fluoro-1,1- dimethyl-isoindolin-2- yl)-N-(2-sulfamoyl-4-pyridyl)-5- (trifluoromethyl) pyridine-3-carboxamide 510.1 510.2 114

2-(azepan-1-yl)-N-(2- methyl-5-sulfamoyl- thiophen-3-yl)-5-(trifluoromethyl)- pyridine-3-carboxamide 463.1 463.2 115

2-(4,4-difluoro-5- methylazepan-1-yl)-N- (2-sulfamoylpyridin-4-yl)-5-(trifluoro- methyl)pyridine-3- carboxamide 494.1 494.3 116

5-chloro-2-[(7R or 7S)- 7-(difluoromethly)-1,4- oxazepan-4-yl]-6-methyl-N-(2- sulfamoylpyridin-4- yl)pyridine-3- carboxamide 476.9 477.0117

5-chloro-2-[(7S or 7R)- 7-(difluoromethyl)-1,4- oxazepan-4-yl]-6-methyl-N-(2- sulfamoylpyridin-4- yl)pyridine-3- carboxamide 476.9 477.0118

(R or S)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4- oxazepan-4- yl)nicotinamide 514.1 514.2 119

(S or R)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4- oxazepan-4- yl)nicotinamide 514.1 514.2 120

2-[(2S,7R or 2R,7S)-2- methyl-7- (trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-pyridine-3-carboxamide 528.1 528.2 121

2-((2R,7S or 2S.7R)-2- methyl-7- (trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-nicotinamide 528.1 528.2 122

2-((2R,7R or 2S,7S)-2- methyl-7- (trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-nicotinamide 528.1 528.2 123

2-((2S,7S or 2R,7R)-2- methyl-7-(trifluoro- methyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoyl- pyridin-4-yl)-5- (trifluoromethyl)- nicotinamide528.1 528.2 124

(S or R)-5-chloro-2-(2- (difluoromethyl)morpho- lino)-6-methyl-N-(2-sulfamoylpyridin-4- yl)nicotinamide 462.9 463.2 125

(R or S)-5-chloro-2-(2- (difluoromethyl)morpho- lino)-6-methyl-N-(2-sulfamoylpyridin-4- yl)nicotinamide 462.9 463.2 126

N-(2-sulfamoylpyridin- 4-yl)-5- (trifluoromethyl)-2- [(2S)-2-(trifluoro-methyl)pyrrolidin-1- yl]pyridine-3- carboxamide 484.1 484.2 150° C. for10 minutes in Step 3 127

(R)-N-(2- sulfamoylpyridin-4-yl)- 5-(trifluoromethyl)-2-(2-(trifluoromethyl) pyrrolidin- 1-yl)nicotinamide 484.1 484.2 150° C. for10 minutes in Step 3 128

N-(2-sulfamoylpyridin- 4-yl)-5- (trifluoromethyl)-2-[3-(trifluoromethyl)- pyrrolidin-1-yl]pyridine- 3-carboxamide 484.1 484.2150° C. for 10 minutes in Step 3 129

(S or R)-2-(3- cyanopyrrolidin-1-yl)-N- (2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)- nicotinamide 441.1 441.2 150° C. for 10 minutesin Step 3, Chiral Method K, peak 2 130

(R or S)-2-(3- cyanopyrrolidin-1-yl)-N- (2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)- nicotinamide 441.1 441.2 150° C. for 10 minutesin Step 3, Chiral Method K, peak 1

Example 1312-(4,4-difluoro-3-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

A tube was charged with2-chloro-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(Intermediate 21, 0.10 g, 0.26 mmol), 4,4-difluoro-5-methylazepanehydrochloride (Intermediate 10, 80 mg crude), DIPEA (0.046 mL, 0.26mmol) and NMP (1 mL). The mixture was heated to 150° C. for 10 min undermicrowave irradiation. Then the mixture was filtered and the filtratewas purified by reverse phase chromatography (37-100% MeCN in water with0.1% 10 mM NH₄CO₃, C18 column) to give the title compound. LRMS m/z(M+H): calculated 494.1, observed 493.9. ¹H NMR δ (ppm) (400 MHz,CD₃OD): 8.57 (d, J=5.6 Hz, 1H), 8.51 (d, J=1.2 Hz, 1H), 8.38 (d, J=1.6Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.84-7.91 (m, 1H), 3.79-3.86 (m, 1H),3.68-3.76 (m, 1H), 3.53-3.60 (m, 1H), 3.37-3.45 (m, 1H), 2.22-2.47 (m,2H), 2.05-2.11 (m, 1H), 1.88-1.95 (m, 2H), 0.94 (d, J=7.2 Hz, 3H).

Example 1322-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

A tube was charged with2-chloro-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(Intermediate 37, 21 mg, 0.16 mmol), DIPEA (0.023 mL, 0.13 mmol) and NMP(2 mL). The mixture was heated to 150° C. for 10 min under microwaveirradiation. Then the mixture was purified by reverse phasechromatography (42-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 480.1, observed 479.9. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.57 (d, J=5.6 Hz, 1H), 8.36 (d, J=1.6 Hz,1H), 7.96 (d, J=7.2 Hz, 1H), 7.86 (dd, J=1.6, 5.6 Hz, 1H), 7.12 (d,J=7.6 Hz, 1H), 3.74 (td, J=2.4, 5.6 Hz, 2H), 3.46 (t, J=5.6 Hz, 2H),2.25-2.46 (m, 2H), 1.84-2.06 (m, 4H).

Examples 133 and 134 2-((2R,6S or2S,6R)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(133) and 2-((2S,6R or2R,6S)-2-ethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(134)

Step 1:N-(2-(N,N-bis(3,4-dimethylbenzyl)sulfamoyl)pyridin-4-yl)-2-((2R,6S and2S,6R)-2-ethyl-6-(trifluoromethyl)morpholino)-5-(trifluoromethyl)nicotinamide

A tube charged with (2R,6S and2S,6R)-2-ethyl-6-(trifluoromethyl)morpholine hydrochloride (Intermediate15, 0.17 g crude),N-(2-(N,N-bis(3,4-dimethylbenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-5-(trifluoro-methyl)nicotinamide(Intermediate 22, 0.11 g, 0.51 mmol), K₂CO₃ (0.16 g, 1.1 mmol) and DMSO(1.5 mL) at 20° C. was sparged with nitrogen for 1 min, then sealed andheated at 80° C. for 12 h. Then the mixture was cooled to roomtemperature, diluted in water and extracted with EtOAc. The organiclayer was washed with brine, dried over by Na₂SO₄, filtered andconcentrated to give the title compound.

Step 2: 2-((2R,6S or2S,6R)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(133) and 2-((2S,6R or2R,6S)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(134)

To a solution ofN-(2-(N,N-bis(3,4-dimethylbenzyl)sulfamoyl)pyridin-4-yl)-2-((2R,6S and2S,6R)-2-ethyl-6-(trifluoromethyl)morpholino)-5-(trifluoromethyl)nicotinamide(0.22 g crude) in dichloromethane (3 mL) was added TFA (1 mL). Themixture was stirred at 15° C. for 3 h, then concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (ethyl acetate/petroleum ether=1/1) to give the titlecompound as a racemic mixture: 2-((2R,6S and2S,6R)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide.The racemic mixture was separated by Chiral-SFC (Phenomenex-Amylose-1,20% EtOH/CO₂) to give two enantiomers: enantiomer A (compound 133); andenantiomer B (compound 134). Enantiomer A: [LRMS m/z (M+H): calculated528.1, observed 528.1; ¹H NMR δ (ppm) (500 MHz, CD₃OD): 8.45-8.52 (m,2H), 8.26-8.29 (m, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.77-7.81 (m, 1H),4.21-4.31 (m, 1H), 3.78-3.90 (m, 2H), 3.54-3.65 (m, 2H), 3.23-3.26 (m,1H), 1.47-1.57 (m, 1H), 1.26-1.36 (m, 1H), 0.74-0.80 (m, 3H)].Enantiomer B: [LRMS m/z (M+H): calculated 528.1, observed 528.2; ¹H NMRδ (ppm) (500 MHz, CD₃OD): 8.44-8.54 (m, 2H), 8.26-8.29 (m, 1H), 8.01 (d,J=2.5 Hz, 1H), 7.77-7.81 (m, 1H), 4.21-4.31 (m, 1H), 3.78-3.90 (m, 2H),3.54-3.65 (m, 2H), 3.22-3.27 (m, 1H), 1.47-1.57 (m, 1H), 1.26-1.36 (m,1H), 0.74-0.80 (m, 3H)].

Examples 135 and 136 (R orS)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(135) and (S orR)-2-(2,2-dimethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(136)

Step 1: (R andS)—N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-5-(trifluoromethyl)nicotinamide

A tube charged withN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-chloro-5-(trifluoromethyl)-nicotinamide(Intermediate 22, 0.16 g, 0.24 mmol),2,2-dimethyl-6-(trifluoromethyl)morpholine hydrochloride (Intermediate16, 0.10 g, 0.46 mmol), K₂CO₃ (0.16 g, 1.1 mmol) and DMSO (1.5 mL) wassparged with nitrogen for 1 min, then sealed and heated to 80° C. for 12h. Then the mixture was cooled to rt, diluted in water and extractedwith EtOAc. The organic layer was washed with brine, dried over byNa₂SO₄, filtered and concentrated to give the title compound.

Step 2: (R orS)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(135) and (S orR)-2-(2,2-dimethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide(136)

To a solution of (R andS)—N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-5-(trifluoromethyl)nicotinamide(0.20 g crude) in dichloromethane (3 mL) was added TFA (1 mL). Themixture was stirred at 15° C. for 3 h. Then the mixture was concentratedunder reduced pressure and purified by silica gel chromatography (ethylacetate/petroleum ether=1/1) to give a racemic mixture of (R andS)-2-(2,2-dimethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide.The racemic material was separated by Chiral-SFC (ChiralPak IC, 15%MeOH/0.1% NH₃—H₂O) to give 2 enantiomers: enantiomer A (compound 135),and enantiomer B (compound 136). Enantiomer A (compound 135): [LRMS m/z(M+H): calculated 528.1, observed 528.1; ¹H NMR δ (ppm) (500 MHz,CD₃OD): 8.63 (d, J=5.5 Hz, 2H), 8.39 (s, 1H), 8.15 (d, J=2.0 Hz, 1H),7.91-7.97 (m, 1H), 4.39-4.47 (m, 1H), 4.14-4.23 (m, 1H), 3.81-3.89 (m,1H), 3.07-3.15 (m, 1H), 3.03 (d, J=13.5 Hz, 1H), 1.24 (d, J=10.0 Hz,6H)]. Enantiomer B (compound 136): [LRMS m/z (M+H): calculated 528.1,observed 528.1; ¹H NMR δ (ppm) (500 MHz, CD₃OD): 8.48-8.52 (m, 2H), 8.27(br s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.78-7.84 (m, 1H), 4.27-4.34 (m,1H), 4.03-4.09 (m, 1H), 3.70-3.76 (m, 1H), 2.95-3.02 (m, 1H), 2.90 (d,J=13.5 Hz, 1H), 1.11 (d, J=10.0 Hz, 6H)].

Example 1374-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide

Step 1: 4-(2-chloro-5-(trifluoromethyl)nicotinamido)picolinamide

To a mixture of 2-chloro-5-(trifluoromethyl)nicotinic acid (0.20 g, 0.89mmol) in pyridine (1 mL) was added 4-amino-pyridine-2-carboxamide (0.12g, 0.89 mmol) and EDC (0.17 g, 0.89 mmol). The mixture was sonicated andheated at 50° C. for 6 hours, then stirred at ambient temperature for2.5 days in a sealed vial. Then the mixture was concentrated under astream of nitrogen with heating to 60° C. to give the title compound.

Step 2:4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide

To a mixture of 4-(2-chloro-5-(trifluoromethyl)nicotinamido)picolinamide(0.31 g, 0.89 mmol) in DMSO (10 mL) was added K₂CO₃ (0.37 g, 2.7 mmol),4,4-difluoroazepane hydrochloride (0.15 g, 0.89 mmol) and DIPEA (0.12 g,0.89 mmol). The mixture was sonicated and stirred at 85° C. for 6 hours.Then the mixture was cooled to rt and diluted with EtOAc. The organiclayer was washed with saturated aqueous NaHCO₃, water, brine, dried overMgSO₄ and concentrated to give a residue that was purified by silica gelchromatography (EtOAc/hexanes) to give the title compound. LRMS m/z(M+H): calculated 444.1, observed 444.1. ¹H NMR δ (ppm) (500 MHz,CDCl₃): 10.03 (s, 1H), 8.53 (m, 3H), 8.36 (s, 1H), 8.07 (d, 1H), 7.93(m, 1H), 5.42 (d, 1H), 3.80 (m, 2H), 3.50 (m, 2H), 2.36 (m, 2H), 1.98(m, 4H) ppm.

TABLE 4 The compounds of Exmples 138-142 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 137.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ 138

6-chloro-2-(4,4- difluoroazepan-1-yl)-N- (2-sulfamoyl-4-pyridyl)pyridine-3- carboxamide 446.1 446.2 139

2-(azepan-1-yl)-N-(2- sulfamoyl-4-pyridyl)-5- (trifluoromethyl)pyridine-3-carboxamide 444.1 444.3 140

2-(azepan-1-yl)-N-(2- methylsulfonyl-4- pyridyl)-5- (trifluoromethyl)-pyridine-3-carboxamide 443.2 443.5 141

2-(azepan-1-yl)-N-(6- sulfamoyl-2-pyridyl)-5- (trifluoromethyl)pyridine-3-carboxamide 444.1 444.3 142

2-(4,4-difluoroazepan-1- yl)-6-methoxy-N-(2- sulfamoylpyridin-4-yl)nicotinamide 442.1 442.1

Example 143N-(2-methoxypyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamide

Step 1:2-chloro-N-(2-methoxypyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a mixture of 2-chloro-5-(trifluoromethyl)nicotinic acid (0.10 g, 0.44mmol) in pyridine (1 mL) was added 4-amino-2-methoxypyridine (0.066 g,0.53 mmol) and EDC (0.13 g, 0.66 mmol). The mixture was sonicated andstirred at ambient temperature for 17 hours in a sealed vial. Then themixture was concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (EtOAc/hexanes) to give thetitle compound.

Step 2:N-(2-methoxypyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-trifluoromethyl)nicotinamide

To a mixture of2-chloro-N-(2-methoxypyridin-4-yl)-5-(trifluoromethyl)nicotinamide (0.12g, 0.89 mmol) in DMF (0.5 mL) was added 6-azaspiro[2.5]octane (84 mg,0.75 mmol), and DIPEA (0.20 g, 1.5 mmol). The mixture was heated at 50°C. for 2 days. Then the mixture was diluted with EtOAc, washed withsaturated aqueous NaHCO₃, water, brine, dried over MgSO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (EtOAc/hexanes) to give the title compound. LRMS m/z(M+H): calculated 407.2, observed 407.2 found; ¹H NMR δ (ppm) (500 MHz,CDCl₃) □□ 10.67 (s, 1H), 8.66 (s, 3H), 8.56 (s, 1H), 8.15 (d, 1H), 7.18(m, 2H), 3.97 (s, 3H), 3.36 (m, 4H), 1.59 (m, 4H), 0.42 (s, 4H) ppm.

TABLE 5 The compounds of Exmples 144-146 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 143.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ 144

2-(4,4-difluoroazepan- 1-yl)-N-(5-sulfamoyl- 3-pyridyl)-5- (trifluoro-methyl)pyridine-3- carboxamide 480.1 480.2 145

2-(azepan-1-yl)-N-(5- sulfamoyl-3-pyridyl)- 5-(trifluoromethyl)pyridine- 3-carboxamide 444.1 444.2 146

2-(4,4-difluoroazepan- 1-yl)-N-(2-methoxy-4- pyridyl)-5-(trifluoro-methyl)pyridine-3- carboxamide 431.2 431.1

Example 1472-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1:2-chloro-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid(1.0 g, 4.4 mmol) and 2-(methylsulfonyl)pyridin-4-amine (0.76 g, 4.4mmol) in pyridine (22 mL) at 0° C. was added POCl₃ (0.45 mL, 4.9 mmol).The mixture was stirred at 0° C. for 1 hour, then quenched with brineand extracted with ethyl acetate. The organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure to give aresidue that was trituated with Et₂O. The resulting solid was collectedand dried under reduced pressure to give the title compound.

Step 2:2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-chloro-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide(50 mg, 0.13 mmol) in NMP (0.66 mL) was added4,4-difluoro-3,5-dimethylpiperidine hydrochloride (24 mg, 0.13 mmol) andDIPEA (69 μl, 0.40 mmol). The mixture was heated at 70° C. for 4 hours.Then the reaction was quenched with aqueous potassium phosphatemonobasic (saturated) and extracted with ethyl acetate. The organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (0-100% EtOAc/hexanes) to give the title compound. LRMSm/z (M+H): calculated 493.1, observed 493.2. ¹H NMR δ (ppm) (600 MHz,DMSO-d₆): 11.30 (s, 1H), 8.67 (d, J=5.4 Hz, 1H), 8.63-8.55 (m, 1H), 8.35(d, J=1.5 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.90 (dd, J=5.5, 1.9 Hz, 1H),4.00-3.89 (m, 2H), 3.25 (s, 3H), 2.83 (t, J=12.8 Hz, 2H), 2.16-2.00 (m,2H), 0.86 (d, J=6.8 Hz, 6H).

TABLE 6 The compounds of Exmples 148-155 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 147.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ Conditions 148

2-[(3R or 3S)-4,4- difluoro-3-methyl-1- piperidyl]-N-(2-methylsulfonyl-4- pyridyl)-5-(trifluoro- methyl)pyridine-3- carboxamide479.1 479.2 Chiral Method G, peak 1 149

2-[(3S or 3R)-4,4- difluoro-3-methyl-1- piperidyl]-N-(2-methylsulfonyl-4- pyridyl)-5-(trifluoro- methyl)pyridine-3- carboxamide479.1 479.2 Chiral Method G, peak 2 150

N-(2-cyano-4- pyridyl)-2-[(3S,5R)- 4,4-difluoro-3,5- dimethyl-1-piperidyl]-5-(tri- fluoromethyl) pyridine- 3-carboxamide 440.1 440.1 151

N-(2-methylsulfonyl- 4-pyridyl)-2- [(1R,5S)-6,6,7,7- tetrafluoro-3-azabicyclo[3.2.0]heptan- 3-yl]-5-(trifluoro- methyl)pyridine-3-carboxamide 513.1 513.1 152

2-[(1R,5S)-3- azabicyclo[3.2.0]heptan- 3-yl]-N-(2- methylsulfonyl-4-pyridyl)-5-(trifluoro- methyl)pyridine-3- carboxamide 441.1 441.1 153

2-[(1R,5S)-3- azabicyclo[3.2.0]heptan- 3-yl]-N-(2-cyano-4-pyridyl)-5-(tri- fluoromethyl)pyridine- 3-carboxamide 388.1 388.1 154

(S or R)-N-(2- cyanopyridin-4-yl)-2- (4,4-difluoro-3- methylpiperidin-1-yl)-5-(trifluoro- methyl)nicotinamide 426.1 426.2 Chiral Method H, peak2 155

(R or S)-N-(2- cyanopyridin-4-yl)-2- (4,4-difluoro-3- methylpiperidin-1-yl)-5-(trifluoro- methyl)nicotinamide 426.4 426.2 Chiral Method H, peak1

Example 156 4-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5(trifluoromethyl)nicotinamido)picolinamide

Step 1: 2-chloro-N-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid(1.0 g, 4.4 mmol) and 4-amino-picolinonitrile (0.53 g, 4.4 mmol) inpyridine (22 mL) at 0° C. was added POCl₃ (0.45 mL, 4.9 mmol). Themixture was stirred at 0° C. for 1 hour, then quenched with brine(saturated) and extracted with ethyl acetate. The organic layer wasdried over MgSO₄, filtered and concentrated under reduced pressure togive a residue that was trituated with Et₂O. The resulting solid wascollected, washed with Et₂O and dried under reduced pressure to give thetitle compound.

Step 2:N-(2-cyanopyridin-4-yl)-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)nicotinamide

To a solution of2-chloro-N-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)nicotinamide (90 mg,0.28 mmol) in NMP (1.4 mL) was added 4,4-difluoro-3,5-dimethylpiperidinehydrochloride (51 mg, 0.28 mmol) and DIPEA (0.14 mL, 0.83 mmol). Themixture was heated at 70° C. for 16 h, then quenched with aqueouspotassium phosphate monobasic (saturated) and extracted with ethylacetate. The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (0-100% EtOAc/hexanes) to give the titlecompound.

Step 3:4-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)-picolinamide

N-(2-cyanopyridin-4-yl)-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)nicotinamide(120 mg, 0.27 mmol) and 1 N NaOH (0.82 mL, 0.82 mmol) were combined inMeOH (1.4 mL). The mixture was heated at 70° C. for 4 hours, thenquenched with water and extracted with DCM. The organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (0-100%EtOAc/hexanes) to give the title compound. LRMS m/z (M+H): calculated458.1, observed 458.2. ¹H NMR δ (ppm) (600 MHz, DMSO-d₆): 11.08 (s, 1H),8.58 (s, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.11 (d, J=2.1 Hz,1H), 8.08 (s, 1H), 7.83 (d, J=3.7 Hz, 1H), 7.63 (s, 1H), 3.97 (d, J=13.6Hz, 2H), 2.82 (t, J=12.5 Hz, 2H), 2.10 (s, 2H), 0.84 (d, J=6.8 Hz, 6H).

TABLE 7 The compounds of Exmples 157-158 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 156.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ Conditions 157

N-(2-carbamoyl-4- pyridyl)-2-[(3R or 3S)-4,4-difluoro-3-methyl-1-piperidyl]- 5-(trifluoromethyl)- pyridine-3- carboxamide 444.4444.2 Chiral Method J, peak 2 158

N-(2-carbamoyl-4- pyridyl)-2-[(3S or 3R)-4,4-difluoro-3-methyl-1-piperidyl]- 5-(trifluoromethyl)- pyridine-3- carboxamide 444.1444.2 Chiral Method J, peak 1

Example 1592-(4,4-difluoropiperidin-1-yl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: tert-butyltert-butyl((4-(2-fluoro-4-methoxynicotinamido)pyridin-2-yl)sulfonyl)carbamate

A solution of 2-fluoro-4-methoxynicotinic acid (0.10 g, 0.58 mmol) andtert-butyl (4-aminopyridin-2-yl)sulfonyl(tert-butyl)carbamate (0.19 g,0.58 mmol) in pyridine (2.9 mL) at 0° C. was treated with POCl₃ (0.060mL, 0.64 mmol) dropwise via a syringe. The mixture was stirred at 0° C.for 1 h, then quenched with brine and diluted with EtOAc. The organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure to give a residue that was purified by silica gelchromatography (0-30% ethyl acetate/hexanes) to give the title compound.

Step 2: tert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-4-methoxynicotinamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of tert-butyltert-butyl((4-(2-fluoro-4-methoxy-nicotinamido)pyridin-2-yl)sulfonyl)carbamate(57 mg, 0.12 mmol) in NMP (0.6 mL) was added 4,4-difluoropiperidine (15μl, 0.13 mmol), followed by K₂CO₃ (33 mg, 0.24 mmol). The mixture wasstirred at 110° C. for 4 h, then cooled to rt, diluted with water andextracted with EtOAc. The aqueous layer was acidified with 1 N HCl andextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated under reduced pressure to give the title compound.

Step 3:2-(4,4-difluoropiperidin-1-yl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution tert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-4-methoxynicotinamido)pyridin-2-yl)sulfonyl)carbamate(0.12 g, 0.12 mmol) in DCM (0.6 mL) was added TFA (0.19 mL, 2.5 mmol).The mixture was stirred at 25° C. for 1 h, then concentrated underreduced pressure. The resulting residue was suspended in NaHCO₃ andextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (0-50% ethyl acetate:ethanol(3:1)/hexanes) to give the title compound. LRMS m/z (M+H): calculated428.1, observed 428.2. ¹H NMR δ (ppm) (500 MHz, DMSO-d₆): 11.09 (s, 1H),8.59 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J=5.8 Hz, 1H), 7.77 (d,J=3.5 Hz, 1H), 7.45 (s, 2H), 6.81 (d, J=5.9 Hz, 1H), 3.83 (s, 3H),3.45-3.39 (m, 4H), 2.01-1.92 (m, 4H).

Examples 160 and 161 5-chloro-6-cyclobutyl-2-((2R,6S or2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(160) and 5-chloro-6-cyclobutyl-2-((2S,6R or2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(161)

To a solution of racemic-(2R,6S and2S,6R)-2-methyl-6-(trifluoromethyl)morpholine ((prepared similar toIntermediate 14, 0.26 mg, 1.6 mmol) in NMP (1 mL) were added2,5-dichloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide(Intermediate 33, 0.25 g, 0.62 mmol) and K₂CO₃ (0.43 g, 3.1 mmol). Themixture was stirred at 200° C. for 0.5 hour under microwave irradiation.Then the mixture was washed with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby reverse phase chromatography (40-100% MeCN in water with 0.1% TFA,C18 column) to give a racemic mixture of 5-chloro-6-cyclobutyl-2-((2R,6Sand2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide.The racemic mixture was separated by Chiral-SFC (Phenomenex-Amylose-1,30% EtOH/CO₂) to give two enantiomers: enantiomer A (compound 160), andenantiomer B (compound 161). Enantiomer A (compound 160): [LRMS m/z(M+H): calculated 534.1, observed 534.3, ¹H NMR δ (ppm) (400 MHz,CD₃OD): 8.57 (d, J=5.6 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 7.82-7.87 (m,2H), 4.40 (dd, J=7.2, 11.2 Hz, 1H), 4.18 (d, J=3.2 Hz, 1H), 4.00 (quin,J=8.4 Hz, 1H), 3.84 (dd, J=3.6, 13.2 Hz, 1H), 3.62 (dd, J=6.8, 13.2 Hz,1H), 3.51 (dd, J=3.2, 12.8 Hz, 1H), 3.14 (dd, J=6.4, 12.8 Hz, 1H),2.31-2.47 (m, 4H), 2.03-2.17 (m, 1H), 1.86-1.99 (m, 1H), 1.15 (d, J=6.0Hz, 3H)]. Enantiomer B (compound 161): [LRMS m/z (M+H): calculated534.1, observed 534.3, ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.57 (d, J=5.6Hz, 1H), 8.38 (d, J=1.6 Hz, 1H), 7.81-7.88 (m, 2H), 4.34-4.45 (m, 1H),4.18 (d, J=3.2 Hz, 1H), 4.00 (quin, J=8.4 Hz, 1H), 3.84 (dd, J=3.6, 13.2Hz, 1H), 3.62 (dd, J=6.4, 13.6 Hz, 1H), 3.51 (dd, J=3.2, 13.2 Hz, 1H),3.14 (dd, J=6.4, 12.8 Hz, 1H), 2.30-2.47 (m, 4H), 2.05-2.16 (m, 1H),1.88-1.99 (m, 1H), 1.11-1.19 (m, 1H), 1.15 (d, J=6.8 Hz, 2H)].

Examples 162 and 163 (R orS)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(162) and (S orR)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(163)

A tube was charged with2-chloro-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(Intermediate 37, 150 mg crude), racemic-4,4-difluoro-3-methylpiperidine(64 mg, 0.47 mmol), DIPEA (0.069 mL, 0.39 mmol) and NMP (2 mL). Themixture was heated to 150° C. for 10 min under microwave irradiation.Then the mixture was purified by reverse phase chromatography (43-100%MeCN in water with 0.1% TFA, C18 column) to give a racemic mixture: (RandS)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-nicotinamide.The racemic mixture was separated by Chiral-SFC (Phenomenex-Cellulose-2,30% EtOH) to give two enantiomers: enantiomer A (compound 162), andenantiomer B (compound 163). Enantiomer A (compound 162): [LRMS m/z(M+H): calculated 480.1, observed 480.1, ¹H NMR δ (ppm) (500 MHz,CD₃OD): 8.63 (d, J=5.5 Hz, 1H), 8.42 (d, J=1.5 Hz, 1H), 8.07 (d, J=7.5Hz, 1H), 7.90 (dd, J=2.0, 5.5 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 3.90-4.02(m, 1H), 3.76-3.86 (m, 1H), 3.28-3.33 (m, 1H), 3.05 (dd, J=11.0, 13.0Hz, 1H), 2.08-2.24 (m, 2H), 1.91-2.06 (m, 1H), 0.99 (d, J=7.0 Hz, 3H)].Enantiomer B (compound 163): [LRMS m/z (M+H): calculated 480.1, observed480.1, ¹H NMR δ (ppm) (500 MHz, CD₃OD): 8.63 (d, J=5.5 Hz, 1H), 8.43 (d,J=1.5 Hz, 1H), 8.01-8.16 (m, 1H), 7.91 (dd, J=2.0, 5.5 Hz, 1H), 7.34 (d,J=7.5 Hz, 1H), 3.90-4.01 (m, 1H), 3.76-3.86 (m, 1H), 3.24-3.32 (m, 1H),3.00-3.12 (m, 1H), 2.11-2.22 (m, 2H), 2.04-1.91 (m, 1H), 1.00 (d, J=7.0Hz, 3H)].

Examples 164 and 165 (S orR)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(164) and (R orS)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(165)

To a solution of2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(racemic mixture of Examples 162 and 163, 0.21 g, 0.43 mmol) inacetonitrile (2.2 mL) at 25° C. was added NCS (70 mg, 0.52 mmol). Themixture was stirred at 80° C. for 2 h, then quenched with water andconcentrated under reduced pressure. The resulting residue was extractedwith EtOAc. The organic layer was washed with NaHCO₃, dried over MgSO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (0-60% ethyl acetate/hexanes) to give racemic mixtureof (S andR)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-nicotinamide.The racemic mixture was separated by SFC (Lux-4, 15% EtOH/CO₂ (100 bar))to give two enantiomers: enantiomer A (compound 164), and enantiomer B(compound 165). Enantiomer A (compound 164): [LRMS m/z (M, M+2):calculated 514.1, observed=514.2, 516.2. ¹H NMR δ (ppm) (500 MHz,DMSO-d₆): 11.31 (s, 1H), 8.65 (d, J=5.4 Hz, 1H), 8.29 (s, 1H), 8.25 (s,1H), 7.83 (d, J=5.4 Hz, 1H), 7.49 (s, 2H), 3.85-3.72 (m, 2H), 3.25-3.21(m, 1H), 3.12-2.92 (m, 1H), 2.14 (m, 2H), 1.99 (m, 1H), 0.89 (d, J=6.8Hz, 3H)]. Enantiomer B (compound 165): [LRMS m/z (M, M+2): calculated514.1, observed=514.2, 516.2. ¹H NMR δ (ppm) (500 MHz, DMSO-d₆): 11.31(s, 1H), 8.65 (d, J=5.4 Hz, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 7.83 (d,J=5.4 Hz, 1H), 7.49 (s, 2H), 3.85-3.72 (m, 2H), 3.25-3.21 (m, 1H),3.12-2.92 (m, 1H), 2.14 (m, 2H), 1.99 (m, 1H), 0.89 (d, J=6.8 Hz, 3H)].

Example 1666-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution of2-chloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide(Intermediate 34, 50 mg crude) in NMP (2 mL) was added(3S,5R)-4,4-difluoro-3,5-dimethylpiperidine hydrochloride (38 mg, 0.20mmol) and DIPEA (0.071 mL, 0.41 mmol). The mixture was stirred at 200°C. for 0.5 hour under microwave irradiation. Then the mixture waspurified by reverse phase chromatography (Phenomenex-Amylose-1, 35%EtOH/0.1% NH₃H₂O) to give the title compound. LRMS m/z (M+H): calculated480.2, observed 480.2. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.57 (d, J=5.6Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 7.81-7.90 (m, 2H), 6.86 (d, J=8.0 Hz,1H), 3.75 (d, J=12.4 Hz, 2H), 3.58-3.67 (m, 1H), 2.90 (t, J=12.4 Hz,2H), 2.26-2.41 (m, 4H), 2.01-2.24 (m, 3H), 1.85-1.99 (m, 1H), 0.98 (d,J=6.6 Hz, 6H).

Examples 167 and 168 6-cyclobutyl-2-((2R,6S or2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(167) and 6-cyclobutyl-2-((2S,6R or2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide(168)

34, 90 mg, 0.24 mmol) in NMP (1.5 mL) was added DIPEA (95 mg, 0.74 mmol)and racemic-(2R,6S and 2S,6R)-2-methyl-6-(trifluoromethyl)morpholinehydrochloride (prepared similar to Intermediate 14, 0.10 g, 0.49 mmol).The mixture was stirred at 200° C. for 0.5 hour under microwaveirradiation. Then the mixture was diluted with DMF and purified byreverse phase chromatography (50-100% MeCN in water with 0.1% TFA, C18column) to give a racemic mixture of 6-cyclobutyl-2-((2R,6S and2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide.The racemic mixture was separated by SFC (Phenomenex-Amylose-1, 30%EtOH/0.1% NH₃*H₂O to give two enantiomers: enantiomer A (compound 167),and enantiomer B (compound 168). Enantiomer A (compound 167) [LRMS m/z(M+H): calculated 500.1, observed 500.2, ¹H NMR (ppm) (400 MHz, CD₃OD):8.56 (d, J=5.6 Hz, 1H), 8.39 (d, J=1.6 Hz, 1H), 7.84-7.86 (m, 1H), 7.81(d, J=7.6 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 4.31-4.47 (m, 1H), 4.14-4.20(m, 1H), 3.82-3.86 (m, 1H), 3.60-3.68 (m, 1H), 3.54-3.59 (m, 1H),3.45-3.49 (m, 1H), 3.08-3.14 (m, 1H), 2.32-2.37 (m, 4H), 2.00-2.18 (m,1H), 1.84-1.98 (m, 1H), 1.14 (d, 1=6.4 Hz, 3H)] and enantiomer B [LRMSm/z (M+H): calculated 500.1, observed 500.1, (M+H): NMR δ (ppm) (400MHz, CD₃OD): 8.56 (d, J=5.6 Hz, 1H), 8.39 (d, J=1.6 Hz, 1H), 7.84-7.86(m, 1H), 7.81 (d, J=8.0 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 4.35-4.47 (m,1H), 4.13-4.25 (m, 1H), 3.81-3.86 (m, 1H), 3.61-3.69 (m, 1H), 3.54-3.59(m, 1H), 3.45-3.49 (m, 1H), 3.08-3.14 (m, 1H), 2.27-2.42 (m, 4H),2.01-2.18 (m, 1H), 1.84-1.99 (m, 1H), 1.14 (d, J=6.0 Hz, 3H)].

Example 1695-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution of2,5-dichloro-6-cyclobutyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide(Intermediate 33, 80 mg, 0.20 mmol) in NMP (1 mL) was added(3S,5R)-4,4-difluoro-3,5-dimethylpiperidine hydrochloride (74 mg, 0.50mmol) and K₂CO₃ (0.14 g, 1.0 mmol). The mixture was stirred at 200° C.for 0.5 h under microwave irradiation. Then the mixture was washed withwater and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by reverse phasechromatography (55-100% MeCN in water with 0.1% TFA, C18 column),followed by SFC (Phenomenex-Amylose-1, 30% EtOH, 0.1% NH₃H₂O) to givethe title compound. LRMS m/z (M+H): calculated 514.1, observed 514.3. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.58 (d, J=5.2 Hz, 1H), 8.39 (d, J=1.6 Hz,1H), 7.82-7.88 (m, 2H), 3.95-4.03 (m, 1H), 3.78 (d, J=12.4 Hz, 2H), 2.92(t, J=12.8 Hz, 2H), 2.32-2.44 (m, 4H), 2.06-2.21 (m, 3H), 1.94 (br s,1H), 0.98 (d, J=7.2 Hz, 6H).

Example 1706-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide

A mixture of tBu Xphos Pd G3 (0.12 g, 0.14 mmol),6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide(Intermediate 27, 0.42 g, 1.5 mmol), sodium 2-methylpropan-2-olate (0.28g, 2.9 mmol), 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide(1.0 g, 1.9 mmol) and THF (6 mL) at 20° C. was sparged with a stream ofnitrogen for 1 min. The tube was sealed and heated to 70° C. for 10 h.Then the mixture was cooled to rt, quenched with water and extractedwith EtOAc. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto give a residue that was purified by silica gel chromatography (0-30%ethyl acetate/petroleum ether) to give the title compound.

Step 2:6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide

To a mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methylnicotinamide(0.45 g, 0.60 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture wasstirred at 15° C. for 16 h. Then the mixture was purified by reversephase chromatography (20-50% MeCN in 0.05% NH₄OH, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 446.1, observed 446.2. ¹HNMR δ (ppm) (500 MHz, CD₃OD): 8.59 (d, J=5.5 Hz, 1H), 8.39 (d, J=2.0 Hz,1H), 7.84 (dd, J=2.0, 5.5 Hz, 1H), 6.92 (s, 1H), 3.44-3.54 (m, 4H), 2.33(s, 3H), 1.86-2.01 (m, 4H).

Example 1712-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 5-bromo-2-(4,4-difluoroazepan-1-yl)nicotinonitrile

To a solution of 5-bromo-2-chloronicotinonitrile (3.0 g, 14 mmol) in NMP(20 mL) were added 4,4-difluoroazepane (2.8 g, 21 mmol) and DIPEA (5.5mL, 41 mmol). The mixture was stirred at 50° C. for 10 hours. Then themixture was diluted in water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue that was purified bysilica gel chromatography (15% EtOAc) to give the title compound.

Step 2: (5-cyano-6-(4,4-difluoroazepan-1-yl)pyridin-3-yl)boronic acid

A mixture of 5-bromo-2-(4,4-difluoroazepan-1-yl)nicotinonitrile (1.5 g,4.7 mmol), PdCl₂(dppf) (0.35 g, 0.47 mmol)), bis(pinacolato)-diboron(2.4 g, 9.5 mmol) and potassium acetate (0.93 g, 9.5 mmol) in dioxane(20 mL) was degassed and backfilled with nitrogen three times. Themixture was heated to 80° C. for 2 h. Then the mixture was cooled to rt,filtered and concentrated to give the title compound.

Step 3: 2-(4,4-difluoroazepan-1-yl)-5-hydroxynicotinonitrile

To a mixture of (5-cyano-6-(4,4-difluoroazepan-1-yl)pyridin-3-yl)boronicacid (1.7 g, 4.6 mmol) in THF (10 mL) and water (10 mL) was addedaqueous KOH (0.26 g, 4.6 mmol) at 0° C., followed by H₂O₂ (0.40 mL, 4.6mmol). The mixture was stirred at 20° C. for 2 hours. Then the mixturewas quenched with aqueous sodium thiosulfate solution, acidified to pH=6with aqueous hydrochloric acid (1.2 N), diluted with water and extractedwith EtOAc. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue thatwas purified by silica gel chromatography (0-26% ethyl acetate/PEgradient) to give the title compound.

Step 4: 2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)nicotinonitrile

2-(4,4-difluoroazepan-1-yl)-5-hydroxynicotinonitrile (1.0 g, 4.0 mmol),K₂CO₃ (1.1 g, 7.9 mmol) and sodium chloro-difluoroacetate (1.2 g, 7.9mmol) in DMF (10 mL) and water (2 mL) was stirred at 110° C. for 10 h.The mixture was diluted with water and extracted with EtOAc. The organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (0-25% ethyl acetate/PE) to give the title compound.

Step 5: 2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)nicotinamide

To a mixture of2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)nicotinonitrile (0.25 g,0.82 mmol) in DMSO (5 mL) was added K₂CO₃ (0.23 g, 1.6 mmol), followedby H₂O₂ (3.0 mL, 34 mmol). The mixture was stirred at 35° C. for 1 hour,then diluted with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (PE/EtOAc=1:1) to give the title compound.

Step 6:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)nicotinamide

A mixture of2-(4,4-difluoroazepan-1-yl)-5-(difluoro-methoxy)nicotinamide (0.10 g,0.31 mmol), 5-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-3-sulfonamide(0.25 g, 0.47 mmol), sodium 2-methylpropan-2-olate (90 mg, 0.93 mmol)and tBuXphos (21 mg, 0.031 mmol) in THF (4 mL) was degassed andbackfilled with nitrogen three times. The mixture was heated to 70° C.for 10 hour. Then the mixture was cooled to rt, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (petroleum ether/ethyl acetate=1/1) to givethe title compound.

Step 7:2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

A solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)nicotinamide(0.21 g, 0.24 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at 20° C.for 1 hour. The mixture was concentrated under reduced pressure andpurified by reverse phase chromatography (35-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 478.1, observed 478.2. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56(d, J=5.2 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H),7.86-7.88 (m, 1H), 7.69 (d, J=2.8 Hz, 1H), 6.50-6.97 (m, 1H), 3.66-3.74(m, 2H), 3.42 (t, J=5.6 Hz, 2H), 2.24-2.39 (m, 2H), 1.85-2.02 (m, 4H).

Example 1725-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2-(4,4-difluoroazepan-1-yl)-6-methylnicotinonitrile

To a solution of 2-chloro-6-methylnicotinonitrile (1.0 g, 6.5 mmol) and4,4-difluoroazepane (1.2 g, 8.5 mmol) in NMP (10 mL) was addedtriethylamine (2.0 g, 20 mmol). The mixture was stirred at 130° C. for 2hours, then diluted in water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether:ethyl acetate=5:1) to givethe title compound.

Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinonitrile

To a mixture of NCS (0.40 g, 3.0 mmol) and2-(4,4-difluoroazepan-1-yl)-6-methylnicotinonitrile (0.50 g, 2.0 mmol)was added a drop of acetic acid in DMF (5 mL). The mixture was stirredat 20° C. for 12 hours. Then the mixture was washed with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (petroleum ether:ethyl acetate=5:1) to give the titlecompound.

Step 3: 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide

To a solution of5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinonitrile (0.32 g,1.1 mmol) in DMSO (8 mL) was added potassium hydroxide (0.25 g, 4.5mmol) and hydrogen peroxide (0.38 g, 11 mmol). The mixture was stirredat 15° C. for 2 hours. Then the mixture was diluted with water andextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (0-20% EtOAc/petroleum ether) togive the title compound.

Step 4:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide

To a solution of5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide (0.45 g, 1.5mmol) in dioxane (1.5 mL) was added Cs₂CO₃ (1.4 g, 4.4 mmol),5-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-3-sulfonamide (1.2 g, 2.2mmol) and XantPhos-Pd-G2 (0.13 g, 0.15 mmol). The reaction mixture wasdegassed and backfilled with nitrogen three times then stirred at 100°C. for 13 hours. Then the mixture was diluted with water and extractedwith EtOAc. The organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue that was purified by silica gel chromatography (petroleumether:ethyl acetate=1:1) to give the title compound.

Step 5:5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylnicotinamide(0.45 g, 0.59 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture wasstirred at 12° C. for 12 hours. Then the mixture was filtered andpurified by reverse phase chromatography (30-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 460.1, observed 460.0. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56(d, J=5.4 Hz, 1H), 8.38 (d, J=1.6 Hz, 1H), 7.85 (dd, J=2.0, 5.4 Hz, 1H),7.76 (s, 1H), 3.68-3.73 (m, 2H), 3.40 (t, J=5.6 Hz, 2H), 2.50 (s, 3H),2.27-2.40 (m, 2H), 1.88-2.04 (m, 4H).

Example 1734-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-sulfamoylpyridin-4-yl)pyrimidine-5-carboxamide

Step 1: 4-(4,4-difluoroazepan-1-yl)-2-methylpyrimidine-5-carbonitrile

To a stirred solution of 4-chloro-2-methylpyrimidine-5-carbonitrile(0.24 g, 1.6 mmol) and 4,4-difluoroazepane hydrochloride (0.32 g, 1.9mmol) in DMF (4 mL) was added DIPEA (0.9 mL, 5.2 mmol) at 20° C. Themixture was stirred at 80° C. for 12 h, then diluted with EtOAc. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give thetitle compound.

Step 2: 4-(4,4-difluoroazepan-1-yl)-2-methylpyrimidine-5-carboxamide

To a stirred solution of4-(4,4-difluoroazepan-1-yl)-2-methylpyrimidine-5-carbonitrile (0.10 g,0.40 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in DMSO (4 mL) wasadded hydrogen peroxide (0.45 g, 4.0 mmol). The mixture was stirred at20° C. for 2 h, then diluted with EtOAc. The organic layer was washedwith water, saturated Na₂SO₃ aqueous solution, brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the title compound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-4-(4,4-difluoroazepan-1-yl)-2-methylpyrimidine-5-carboxamide

A mixture of4-(4,4-difluoroazepan-1-yl)-2-methylpyrimidine-5-carboxamide (30 mg,crude), 4-bromo-N,N-bis(2,4-dimethoxybenzyl)-pyridine-2-sulfonamide (66mg, 0.12 mmol), Cs₂CO₃ (0.11 g, 0.33 mmol), and XantPhos-Pd-G2 (10 mg,0.011 mmol) in dioxane (2.0 mL) was degassed and backfilled withnitrogen three times. The mixture was heated to 100° C. for 12 h, thencooled to 20° C. and diluted with EtOAc. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound.

Step 4:4-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-sulfamoylpyridin-4-yl)pyrimidine-5-carboxamide

To a stirred solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-4-(4,4-difluoroazepan-1-yl)-2-methylpyrimidine-5-carboxamide(60 mg crude) in DCM (4 mL) was added TFA (1 mL). The mixture wasstirred at 20° C. for 2 h, then the solvent was removed under reducedpressure to give a residue that was purified by reverse phasechromatography (63-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 427.1, observed 427.1. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.61 (s, 2H), 8.35 (d, J=2.0 Hz, 1H), 7.85(dd, J=5.6, 2.0 Hz, 1H), 3.98 (br s, 2H), 3.67 (br s, 2H), 2.64 (s, 3H),2.37 (br s, 2H), 1.97-2.10 (m, 4H).

Example 1742-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: (Z)-4-ethoxy-1,1-difluorobut-3-en-2-one

A mixture of ethoxyethene (2.0 g, 28 mmol), N,N-dimethylpyridin-4-amine(0.20 g, 1.7 mmol) and 2,2-difluoroacetic anhydride (4.8 g, 28 mmol) indichloromethane (50 mL) was stirred at 20° C. for 16 h. Then the mixturewas dissolved in water and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-30% ethyl acetate/petroleumether) to give the title compound.

Step 2: 6-(difluoromethyl)-2-hydroxynicotinonitrile

(Z)-4-ethoxy-1,1-difluorobut-3-en-2-one (2.5 g, 17 mmol),2-cyanoacetamide (2.1 g, 25 mmol) and sodium ethanolate (1.2 g, 18 mmol)were added to EtOH (20 mL). The mixture was heated to 90° C. for 12 h.Then the mixture was concentrated to give the title compound.

Step 3: 2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)nicotinonitrile

A mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 g, 12 mmol),6-(difluoromethyl)-2-hydroxynicotinonitrile (1 g crude),6-(difluoromethyl)-2-hydroxynicotinonitrile (1 g crude),benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate(0.52 g, 1.2 mmol) and 4,4-difluoroazepane hydrochloride (0.30 g, 1.8mmol) in acetonitrile (2 mL) was stirred at 20° C. for 16 h. Then themixture was purified by silica gel chromatography (petroleum ether/ethylacetate=10/1) to give the title compound.

Step 4: 2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)nicotinamide

A mixture of K₂CO₃ (87 mg, 0.63 mmol),2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)nicotinonitrile (60 mg,0.21 mmol) and hydrogen peroxide (120 mg, 1.0 mmol) in DMSO (1 mL) wasstirred at 20° C. for 2 h. Then the mixture was diluted in water andsaturated Na₂SO₃ and extracted with EtOAc. The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound.

Step 5:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)nicotinamide

A mixture of 4-bromo-N,N-bis(2,4-dimethoxybenzyl)-pyridine-2-sulfonamide (92 mg, 0.17 mmol),XantPhos Pd G2 (10 mg, 0.011 mmol), Cs₂CO₃ (110 mg, 0.34 mmol) and2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)nicotinamide (35 mg, 0.12mmol) in dioxane (2 mL) was degassed and backfilled with nitrogen threetimes. The mixture was heated to 100° C. for 6 h. Then the mixture waspurified by silica gel chromatography (petroleum ether/ethylacetate=2/1) to give the title compound.

Step 6:2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

A mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoro-azepan-1-yl)-6-(difluoromethyl)nicotinamide(22 mg, 0.029 mmol) in dichloromethane (1 mL) and TFA (1 mL) was stirredat 20° C. for 2 h. Then solvent was concentrated under reduced pressureto give a residue that was purified by by reverse phase chromatography(20-50% MeCN in water with 0.05% NH₄OH, C18 column) to give the titlecompound. LRMS m/z (M+H): calculated 462.1, observed 462.2. ¹H NMR δ(ppm) (500 MHz, CD₃OD): 8.52-8.62 (m, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.94(d, J=7.5 Hz, 1H), 7.88 (dd, J=2.0, 5.5 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H),6.40-6.71 (m, 1H), 3.75 (dd, J=2.5, 5.5 Hz, 2H), 3.46 (t, J=5.5 Hz, 2H),2.24-2.41 (m, 2H), 1.87-2.03 (m, 4H).

Example 1752-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1: tert-butyltert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

A mixture of2-(4,4-difluoropiperidin-1-yl)-5-(trifluoro-methyl)nicotinamide(Intermediate 20, 38 g, 123 mmol), tert-butyl(4-bromopyridin-2-yl)sulfonyl(tert-butyl)carbamate (51 g, 130 mmol),Brettphos-Pd-G3 (1.1 g, 1.2 mmol), cesium carbonate (60 g, 180 mmol) anddioxane was degassed with nitrogen sparge. The mixture was heated to 90°C. for 1 h. Then the mixture was cooled to rt, diluted in EtOAc andfiltered. The organic layer was washed with citric acid, brine, driedover Na₂SO₄, filtered and concentrated to give the title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

To a solution of tert-butyltert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate (80 g, 103 mmol) in DCM wasadded dropwise sulfuric acid (80 mL, 103 mmol). The mixture was stirredat rt for 1 h. Then the mixture was decanted into a solution of NH₄HCO₃,and filtered. The filtrate was extracted with DCM. The organic layer wasevaporated and combined with filter cake. The resulting solid wasdissolved in AcCN at 60° C., then water was added and the AcCNevaporated off, and the mixture was filtered to give the title compound.LRMS m/z (M+H): calculated 466.1, observed 466.0 (and 504 [M+K]). ¹H NMRδ (ppm) (400 MHz, DMSO-d₆): 11.22 (1H, s), 8.64 (2H, d), 8.32 (1H, d),8.18 (1H, d), 7.87 (1H, m), 7.47 (2H, s), 3.63 (4H, m), 2.12-1.98 (4H,m).

Example 1764-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonicacid

To a vial of2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide(Example 175, 80 mg, 0.17 mmol), potassium carbonate (47 mg, 0.34 mmol),2-mesityl-2,5,6,7-tetrahydropyrrolo[2,1-c][1,2,4]triazol-4-ium chloride(2.3 mg, 8.6 μmol) and water (0.16 mL, 8.6 mmol) were added DMF (0.86mL) and benzaldehyde (21 μl, 0.21 mmol). The vial was sealed and heatedat 80° C. for 16 h. Then the mixture was concentrated under reducedpressure and purified by reverse phase chromatography (10%-100% MeCN inwater with 0.1% TFA, C18 column) to give the title compound. LRMS m/z(M+H): calculated 466.4, observed 466.7. ¹H NMR δ (ppm) (500 MHz,CD₃OD): 8.55 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.92 (s,1H), 3.70-3.63 (m, 4H), 2.04 (tt, J=13.6, 5.6 Hz, 4H).

Example 1772-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethoxy)nicotinamide

Step 1: 4,4-difluoro-1-(5-(trifluoromethoxy)pyridin-2-yl)azepane

To a solution of 2-bromo-5-(trifluoromethoxy)pyridine (0.30 g, 1.2 mmol)in THF (3 mL) was added 4,4-difluoroazepane (0.25 g, 1.9 mmol), sodium2-methylpropan-2-olate (0.36 g, 3.7 mmol) and Brettphos-Pd-G3 (0.17 g,1.2 mmol) at 25° C. under a nitrogen atmosphere. The mixture was stirredat 60° C. for 12 h. Then the mixture was diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gel columnchromatography (5-20% petroleum ether/ethyl acetate) to give the titlecompound.

Step 2: 1-(3-bromo-5-(trifluoromethoxy)pyridin-2-yl)-4,4-difluoroazepane

To a solution of4,4-difluoro-1-(5-(trifluoromethoxy)pyridin-2-yl)azepane (0.20 g, 0.67mmol) in DCM (3 mL) was added NBS (0.12 g, 0.67 mmol). The mixture wasstirred at 20° C. for 10 h. Then the mixture was diluted with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gel columnchromatography (5-20% petroleum ether/ethyl acetate) to give the titlecompound.

Step 3: 2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethoxy)nicotinonitrile

A solution of1-(3-bromo-5-(trifluoromethoxy)pyridin-2-yl)-4,4-difluoroazepane (0.12g, 0.32 mmol) in NMP (3 mL) was added Zn(CN)₂ (0.19 g, 1.6 mmol),Pd(tBu₃P)₂ (16 mg, 0.032 mmol) at 20° C. was degassed and backfilledwith nitrogen three times, then the tube was sealed. The mixture washeated at 140° C. under microwave irradiation for 40 minutes. Then themixture was dissolved in water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue that was purified by silicagel chromatography (10% PE/ethyl acetate) to give the title compound.

Step 4: 2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethoxy)nicotinamide

To a solution of2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethoxy)nicotinonitrile (80 mg,0.25 mmol) in DMSO (3 mL) was added K₂CO₃ (0.10 g, 0.75 mmol) andhydrogen peroxide (0.5 mL, 0.25 mmol). The mixture was stirred at 20° C.for 2 h. The mixture was quenched with aqueous Na₂SO₃, diluted withwater and extracted with EtOAc. The organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (50% PE/ethyl acetate) to give the title compound.

Step 5:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethoxy)nicotinamide

To a solution of2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethoxy)nicotinamide (30 mg,0.088 mmol) in dioxane (2 mL) was added4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (52 mg, 0.097mmol), cesium carbonate (86 mg, 0.26 mmol) and Brettphos-Pd-G3 (80 mg,0.088 mmol) at 20° C. under an atmosphere of nitrogen. The mixture wasstirred at 100° C. for 12 h. Then the mixture was diluted in water andextracted with EtOAc. The organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (50% petroleumether/ethyl acetate) to give the title compound.

Step 6:2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethoxy)-nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethoxy)nicotinamide(30 mg, 0.038 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture wasstirred at 20° C. for 10 h then filtered and concentrated under reducedpressure to give a residue that was purified by reversed phasechromatography (MeCN in water with 0.1% TFA, C18 column) to give thetitle compound. LRMS m/z (M+H): calculated 496.1, observed 496.2. ¹H NMRδ (ppm) (400 MHz, CD₃OD): 8.56 (d, J=5.6 Hz, 1H), 8.37 (d, J=1.6 Hz,1H), 8.24 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.6, 2.0 Hz, 1H), 7.78 (d,J=2.0 Hz, 1H), 3.67-3.77 (m, 2H), 3.43 (t, J=5.6 Hz, 2H), 2.24-2.40 (m,2H), 1.86-2.08 (m, 4H).

Example 1782-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 6-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylpyridine

To a stirred solution of 6-chloro-3-fluoro-2-methylpyridine (0.50 g, 3.4mmol), and 4,4-difluoropiperidine hydrochloride (0.65 g, 4.1 mmol) indioxane (10 mL) were added t-BuONa (0.99 g, 10 mmol) and Ruphos-Pd-G3(0.29 g, 0.34 mmol) at 15° C. under a nitrogen atmosphere. The mixturewas stirred at 110° C. for 12 h. Then the mixture was filtered throughCelite™ and the filtrate was concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography(EtOAc/hexane) to give the title compound.

Step 2: 3-bromo-2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylpyridine

To a solution of6-(4,4-difluoropiperidin-1-yl)-3-fluoro-2-methylpyridine (60 mg, 0.26mmol) in acetonitrile (2 mL) was added NBS (56 mg, 0.31 mmol) at 0° C.The mixture was stirred at 0° C. for 2 h. Then the mixture wasconcentrated under reduced pressure, diluted with water and extractedwith EtOAc. The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue that was purified bysilica gel chromatography (petroleum ether/ethyl acetate=10:1) to givethe title compound.

Step 3: 2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylnicotinonitrile

To a stirred solution of3-bromo-2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylpyridine (20 mg,0.065 mmol) in NMP (2 mL) was added dicyanozinc (38 mg, 0.32 mmol), andPd(tBu₃P)₂ (6.6 mg, 0.013 mmol) at 15° C. under nitrogen. The mixturewas stirred at 130° C. under microwave irradiation for 30 min. Then themixture was cooled to room temperature and diluted with EtOAc. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (petether/EtOAc=10:1) to give the title compound.

Step 4: 2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylnicotinamide

To a solution of2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylnicotinonitrile (15 mg,0.059 mmol) in DMSO (2 mL) was added KOH (16 mg, 0.29 mmol) and 30% H₂O₂(0.060 mL, 0.59 mmol). The mixture was stirred at 15° C. for 1 h, thenthe mixture was quenched with saturated Na₂SO₃ and extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue,which was purified by silica gel chromatography (petroleum ether/ethylacetate=1:1) to give the title compound.

Step 5:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylnicotinamide

A mixture of 4-bromo-N,N-bis(2,4-dimethoxybenzyl)-pyridine-2-sulfonamide(0.28 g, 0.53 mmol),2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylnicotinamide (0.12 g,0.44 mmol), Cs₂CO₃ (0.43 g, 1.3 mmol) and Xantphos Pd G2 (39 mg, 0.044mmol) in dioxane (5 mL) was heated to 100° C. for 12 h under anatmosphere of nitrogen. Then the mixture was cooled to room temperatureand diluted with EtOAc. The organic layer was washed with water, brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (pet ether/EtOAc=1:1) to give the title compound.

Step 6:2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methylnicotinamide(0.24 g, 0.33 mmol) in dichloromethane (5 mL) was added TFA (2 mL). Themixture was stirred at 20° C. for 1.5 h, then concentrated under reducedpressure to give a residue that was purified by reverse phasechromatography (35-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 430.1, observed 430.2. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.59 (d, J=5.4 Hz, 1H), 8.45 (d, J=1.7 Hz,1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 3.43-3.37 (m,4H), 2.47 (d, J=2.7 Hz, 3H), 2.18-1.95 (m, 4H).

Example 1793-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Step 1: 4,4-difluoro-1-(6-(trifluoromethyl)pyridazin-3-yl)azepane

A mixture of 4,4-difluoroazepane hydrochloride (0.34 g, 2.0 mmol), DIPEA(0.86 mL, 4.9 mmol), 3-chloro-6-(trifluoromethyl)pyridazine (0.30 g, 1.6mmol) and NMP (5 mL) was sealed in a tube and heated to 150° C. for 10minutes by microwave irradiation. Then the mixture was cooled to rt,diluted with water and extracted with ethyl acetate. The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (0-30% petroleum ether/ethyl acetate) to give the titlecompound.

Step 2:1-(4-bromo-6-(trifluoromethyl)pyridazin-3-yl)-4,4-difluoroazepane

A mixture of 4,4-difluoro-1-(6-(trifluoromethyl)pyridazin-3-yl)azepane(0.30 g, 1.1 mmol) and 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione(0.91 g, 3.2 mmol) in acetic acid (5 mL) was stirred at 40° C. for 18 h.The mixture was cooled to rt, diluted in water and extracted with ethylacetate. The combined organic fractions were dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (0-10% petroleum ether/ethylacetate) to give the title compound.

Step 3:3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carbonitrile

To a solution of1-(4-bromo-6-(trifluoromethyl)pyridazin-3-yl)-4,4-difluoroazepane (0.15g, 0.42 mmol) in DMA (2 mL) was added dicyanozinc (0.25 g, 2.1 mmol),dppf (46 mg, 0.083 mmol) and Pd₂(dba)₃ (38 mg, 0.042 mmol) at 20° C. Themixture was degassed and backfilled with nitrogen three times, thenstirred at 160° C. for 1 h. Then the mixture was diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (PE/ethylacetate=3/1) to give the title compound.

Step 4:3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

To a solution of3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carbonitrile(0.11 g, 0.36 mmol) in DMSO (2 mL) was added K₂CO₃ (0.25 g, 1.8 mmol),and hydrogen peroxide (0.12 g, 3.6 mmol). The mixture was stirred at 20°C. for 1 h, then diluted with water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (petroleum ether/ethylacetate=1/1) to give the title compound.

Step 5:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-6-(trifluoromethyl)pyridazine-4-carboxamide

To a solution of4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (80 mg, 0.15mmol) in dioxane (10 mL) was added3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide(40 mg, 0.12 mmol), Cs₂CO₃ (40 mg, 0.12 mmol) and Xantphos-Pd-G2 (11 mg,0.012 mmol). The mixture was degassed with nitrogen and stirred at 100°C. for 12 h. Then the mixture was diluted with water and extracted withEtOAc. The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (50% EtOAc/petroleum ether) togive the title compound.

Step 6:3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

To a mixture ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-3-(4,4-difluoroazepan-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide(70 mg, 0.090 mmol) in dichloromethane (2 mL) was added TFA (1 mL, 13mmol). The mixture was stirred at 20° C. for 2 h. Then the mixture wasconcentrated under reduced pressure to give a residue that was purifiedby reverse phase chromatography (25-100% MeCN in water with 0.1% TFA,C18 column) to give the title compound. LRMS m/z (M+H): calculated481.1, observed 481.2. ¹H NMR δ (ppm) (500 MHz, CD₃OD): 8.63 (d, J=5.5Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 7.98-8.11 (m, 1H), 7.90 (dd, J=1.5, 5.5Hz, 1H), 3.98 (td, J=2.5, 5.5 Hz, 2H), 3.61 (t, J=5.5 Hz, 2H), 2.33-2.54(m, 2H), 1.93-2.18 (m, 4H).

Example 1805-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 3-(tert-butyl)-6-chloro-2-methylpyridine

To a stirred solution of copper(I) bromide (2.9 g, 20 mmol) in THF (27mL) at −78° C. was added tert-butylmagnesium chloride (25 mL, 42 mmol).The mixture was stirred at −78° C. for 30 minutes, then3-bromo-6-chloro-2-methylpyridine (1.0 g, 5.0 mmol) in THF (3 mL) wasdropwise added at −78° C. The mixture was stirred at −78° C. for 2 h,then stirred at 20° C. for 24 h. Then the reaction mixture was quenchedwith saturated NH₄Cl aqueous solution at 0° C. and extracted with EtOAc.The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (petroleum ether/ethylacetate=20:1) to give the title compound.

Step 2: 3-(tert-butyl)-6-(4,4-difluoropiperidin-1-yl)-2-methylpyridine

To a stirred solution of 3-(tert-butyl)-6-chloro-2-methylpyridine (40mg, 0.22 mmol) in dioxane (4 mL) under an atmosphere of nitrogen wasadded 4,4-difluoropiperidine hydrochloride (58 mg, 0.37 mmol), sodiumtert-butoxide (95 mg, 0.99 mmol) and RuPhos-Pd-G3 (22 mg, 0.026 mmol).The mixture was stirred at 110° C. for 5 h, then cooled to roomtemperature and diluted with EtOAc. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give the title compound.

Step 3:3-bromo-5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyridine

To a stirred solution of3-(tert-butyl)-6-(4,4-difluoropiperidin-1-yl)-2-methylpyridine (35 mgcrude) in dichloromethane (3 mL) was added NBS (28 mg, 0.16 mmol). Themixture was stirred at 20° C. for 30 minutes. Then the mixture wasconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether/ethyl acetate=10:1) togive the title compound.

Step 4:5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinonitrile

To a stirred solution of3-bromo-5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylpyridine(40 mg, 0.12 mmol) in DMA (3 mL) were added dppf (25 mg, 0.045 mmol),dicyanozinc (45 mg, 0.38 mmol) and Pd₂ (dba)₃ (21 mg, 0.023 mmol) undera nitrogen atmosphere. The mixture was stirred at 140° C. for 4 h, thencooled to room temperature and diluted with EtOAc. The organic layer waswashed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (petroleum ether/ethylacetate=20:1) to give the title compound.

Step 5:5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

To a stirred solution of5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinonitrile(40 mg) and potassium carbonate (60 mg, 0.43 mmol) in DMSO (2 mL) wasadded hydrogen peroxide (0.16 g, 1.4 mmol). The mixture was stirred at20° C. for 3 h then diluted with EtOAc. The organic layer was washedwith water, brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound.

Step 6:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide

A mixture of5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide (26mg, crude), 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide(54 mg, 0.10 mmol), Cs₂CO₃ (82 mg, 0.25 mmol), and XantPhos-Pd-G2 (6.0mg, 6.8 μmol) in dioxane (1.2 mL) was degassed and backfilled withnitrogen three times. The mixture was heated to 100° C. for 12 h, thencooled to rt and diluted with EtOAc. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give the title compound.

Step 7:5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a stirred solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methylnicotinamide(42 mg, crude) in DCM (3 mL) was added TFA (0.8 mL). The mixture wasstirred at 20° C. for 2 h, then concentrated under reduced pressure togive a residue that was purified by reverse phase chromatography(50-100% MeCN in water with 0.1% TFA, C18 column) to give the titlecompound. LRMS m/z (M+H): calculated 468.2, observed 468.2. ¹H NMR δ(ppm) (400 MHz, CD₃OD): 8.58 (d, J=5.2 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H),8.11 (br s, 1H), 7.86 (dd, J=5.2, 2.0 Hz, 1H), 3.47 (br s, 4H), 2.73 (s,3H), 1.99-2.18 (m, 4H), 1.44 (s, 9H).

Example 1815-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide

Step 1: 2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)pyridine

To a solution of 2-chloro-6-(trifluoromethyl)pyridine (0.30 g, 1.7 mmol)in DMA (6 mL) was added 4,4-difluoropiperidine hydrochloride (0.31 g,2.0 mmol) and DIPEA (0.87 mL, 5.0 mmol). The mixture was stirred at 120°C. for 12 h under nitrogen, then diluted with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to give a residue that waspurified by silica gel chromatography (petroleum ether/ethylacetate=10:1) to give the title compound.

Step 2:3-bromo-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine

To a solution of2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)pyridine (0.95 g, 3.6mmol) in MeOH (20 mL) was added 1-bromopyrrolidine-2,5-dione (0.76 g,4.3 mmol) at 0° C. The mixture was stirred at 15° C. for 2 h, thenconcentrated under reduced pressure, diluted with water and extractedwith EtOAc. The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue that was purified bysilica gel chromatography (2% EtOAc) to give the title compound.

Step 3:3-cyclopropyl-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine

To a solution of3-bromo-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine (0.25mg, 0.72 mmol) in dioxane (3 mL) and water (3 mL) was added potassiumcyclopropyltrifluoroborate (0.21 g, 1.4 mmol), Pd(dppf)Cl₂ (53 mg, 0.072mmol) and K₂CO₃ (0.20 g, 1.4 mmol). The mixture was degassed withnitrogen and stirred at 100° C. for 12 h. The mixture was then filteredthrough Celite™ and the filtrate was concentrated. The resulting residuewas diluted with water and extracted with EtOAc. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated togive a residue that was purified by silica gel chromatography (petroleumether:EtOAc=10:1) to give the title compound.

Step 4:3-bromo-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)pyridine

To a solution of3-cyclopropyl-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine(100 mg, 0.33 mmol) in DMF (2 mL) was added NBS (70 mg, 0.39 mmol). Themixture was stirred at rt for 2 h. The solution was diluted with water,and extracted with EtOAc. The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated to a residue that was purified bysilica gel chromatography (petroleum ether/ethyl acetate=10:1) to givethe title compound.

Step 5:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinonitrile

To a mixture of3-bromo-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)pyridine(180 mg, 0.47 mmol), zinc (31 mg, 0.47 mmol), dicyanozinc (140 mg, 1.2mmol) in DMF (5 mL) was added dppf (52 mg, 0.093 mmol) and Pd₂(dba)₃ (43mg, 0.047 mmol) at 20° C. under nitrogen. The reaction mixture washeated to 160° C. for 2 h, then cooled to rt, quenched with H₂O andextracted with EtOAc. The organic layer was separated, washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate=10:1) to give the titlecompound.

Step 6:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinamide

To a solution of5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinonitrile(0.13 g, 0.39 mmol) in DMSO (4 mL) was added KOH (0.11 g, 2.0 mmol) andH₂O₂ (0.40 mL, 3.9 mmol). The mixture was stirred at 15° C. for 1 h,then quenched with water and extracted with EtOAc. The organic layerswas separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to a residue that was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1:1) to givethe title compound.

Step 7:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinamide

In a glovebox, a mixture of4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (92 mg, 0.17mmol),5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)nicotinamide(50 mg, 0.14 mmol), Cs₂CO₃ (0.14 g, 0.43 mmol) and Xantphos Pd G2 (13mg, 0.014 mmol) in dioxane (3 mL) was heated to 100° C. for 12 h. Thenthe mixture was cooled to room temperature and diluted with EtOAc. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (petroleumether:EtOAc=1:1) to give the title compound.

Step 8:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide(181)

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)-sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethyl)-nicotinamide(0.11 g, 0.14 mmol) in dichloromethane (3 mL) was added TFA (1 mL). Themixture was stirred at 20° C. for 1.5 h, then concentrated under reducedpressure to give a residue that was purified by reverse phasechromatography (42-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 506.1, observed 506.1. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.60 (d, J=5.4 Hz, 1H), 8.40 (d, J=7.2 Hz,1H), 7.88 (dd, J=5.4, 2.0 Hz, 1H), 7.68 (s, 1H), 3.57-3.46 (m, 4H),2.22-2.09 (m, 1H), 2.08-1.92 (m, 4H), 1.12-0.98 (m, 2H), 0.84-0.73 (m,2H).

Example 1825-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethoxy)nicotinamide

Step 1: 6-chloro-3-iodo-2-(trifluoromethoxy)pyridine

To a stirred solution of 2-chloro-6-(trifluoromethoxy)pyridine (0.20 mg,1.0 mmol) in THF (6 mL) was added lithium diisopropylamide (1.1 mL, 1.3mmol) at −78° C. The mixture was stirred at −78° C. for 1 h, then asolution of diiodine (0.28 g, 1.1 mmol) in THF (1.0 mL) was added at−78° C. The mixture was warmed to 20° C. for 2 h, then diluted withEtOAc. The organic layer was washed with saturated Na₂SO₃ aqueoussolution, brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether/ethyl acetate=20:1) togive the title compound.

Step 2: 6-chloro-3-cyclopropyl-2-(trifluoromethoxy)pyridine

To a stirred solution of 6-chloro-3-iodo-2-(trifluoromethoxy)pyridine(0.20 g, 0.62 mmol) in toluene (5 mL) and water (0.6 mL) was addedpotassium carbonate (0.26 g, 1.9 mmol), potassiumcyclopropyltrifluoroborate (0.16 g, 1.1 mmol) and Pd(PPh₃)₄ (75 mg,0.065 mmol) at 20° C. under a nitrogen atmosphere. The mixture wasstirred at 110° C. for 12 h, then cooled to room temperature and dilutedwith EtOAc. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate=20:1) to give the titlecompound.

Step 3:3-cyclopropyl-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethoxy)pyridine

To a stirred solution of6-chloro-3-cyclopropyl-2-(trifluoromethoxy)pyridine (0.10 g, 0.42 mmol)in dioxane (5 mL) was added 4,4-difluoropiperidine hydrochloride (0.11g, 0.72 mmol), sodium 2-methylpropan-2-olate (0.12 g, 1.3 mmol) andRuPhos-Pd-G2 (50 mg, 0.060 mmol) under nitrogen atmosphere at 20° C. Themixture was stirred at 110° C. for 12 h, then cooled to room temperatureand diluted with EtOAc. The organic layer was separated, washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate=20:1) to give the titlecompound.

Step 4:3-bromo-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)pyridine

To a stirred solution of3-cyclopropyl-6-(4,4-difluoropiperidin-1-yl)-2-(trifluoromethoxy)pyridine(0.15 g, 0.46 mmol) in DCM (5 mL) was added NBS (91 mg, 0.51 mmol). Themixture was stirred at 20° C. for 30 min. Then the mixture solvent wasremoved under reduced pressure. The resulting residue was dissolved intoEtOAc, and the EtOAc solution was washed with water, brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the title compound.

Step 5:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)nicotinonitrile

To a stirred solution of3-bromo-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)-pyridine(150 mg, crude) in DMA (5 mL) was added dppf (42 mg, 0.076 mmol),dicyanozinc (0.13 g, 1.1 mmol), Pd₂(dba)₃ (35 mg, 0.038 mmol) under anitrogen atmosphere at 20° C. The mixture was stirred at 140° C. for 4h, then cooled to room temperature and diluted with EtOAc. The organiclayer was washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (petroleum ether/ethylacetate=20:1) to give the title compound.

Step 6:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)nicotinamide

To a stirred solution of5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)-nicotinonitrile(50 mg, 0.14 mmol) in DMSO (1.5 mL) was added potassium carbonate (60mg, 0.43 mmol) and hydrogen peroxide (0.16 g, 1.4 mmol). The mixture wasstirred at 20° C. for 30 min, then diluted with EtOAc. The organic layerwas separated, washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give thetitle compound.

Step 7:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)nicotinamide

A mixture of5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)nicotinamide(20 mg, crude),4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (36 mg, 0.067mmol), Cs₂CO₃ (55 mg, 0.17 mmol), and XantPhos-Pd-G2 (6.0 mg, 6.7 μmol)in dioxane (1.2 mL) was degassed and backfilled with nitrogen threetimes. The mixture was heated to 100° C. for 12 h, then cooled to roomtemperature and diluted with EtOAc. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give the title compound.

Step 8:5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethoxy)nicotinamide

To a stirred solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-(trifluoromethoxy)nicotinamide(40 mg, crude) in DCM (2 mL) was added TFA (0.5 mL). The mixture wasstirred at 20° C. for 2 h. Then the solvent was removed at reducedpressure to give a residue that was purified by reverse phasechromatography (52-100% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 522.1, observed 522.1. ¹HNMR δ (ppm) (400 MHz, CD₃OD): 8.57 (d, J=5.6 Hz, 1H), 8.39 (d, J=1.6 Hz,1H), 7.85 (dd, J=5.6, 2.0 Hz, 1H), 7.64 (s, 1H), 3.47 (t, J=5.6 Hz, 4H),1.90-2.10 (m, 5H), 0.95-1.03 (m, 2H), 0.68-0.76 (m, 2H).

Example 1832-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(2,2,2-trifluoroethoxy)nicotinamide

Step 1: 6-iodo-2-methyl-3-(2,2,2-trifluoroethoxy)pyridine

To a solution of 6-iodo-2-methylpyridin-3-ol (0.40 g, 1.7 mmol) in DMF(10 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.51g, 2.2 mmol) dropwise at 0° C. The mixture was stirred at 20° C. for 3h, then washed with water and extracted with EtOAc. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate=5:1) to give the titlecompound.

Step 2:6-(4,4-difluoropiperidin-1-yl)-2-methyl-3-(2,2,2-trifluoroethoxy)pyridine

To a solution of 6-iodo-2-methyl-3-(2,2,2-trifluoroethoxy)pyridine (0.30g, 0.95 mmol) in dioxane (3 mL) was added 4,4-difluoropiperidinehydrochloride (0.18 g, 1.1 mmol), Ruphos-Pd-G3 (79 mg, 0.095 mmol) andsodium 2-methylpropan-2-olate (0.27 g, 2.8 mmol) under nitrogen. Themixture was stirred at 60° C. for 12 h. Then the mixture was washed withwater and extracted with EtOAc. The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue that was purified by silica gel chromatography (petroleumether/ethyl acetate=5:1) to give the title compound.

Step 3:2-(4,4-difluoropiperidin-1-yl)-3-iodo-6-methyl-5-(2,2,2-trifluoroethoxy)pyridine

To a solution of6-(4,4-difluoropiperidin-1-yl)-2-methyl-3-(2,2,2-trifluoroethoxy)pyridine(10 mg, 0.032 mmol) in dichloromethane (2 mL) was added NIS (18 mg,0.081 mmol). The mixture was stirred at 20° C. for 5 h. Then the mixturewas concentrated under reduced pressure to give a residue that waspurified by silica gel chromatography (petroleum ether/ethylacetate=5:1) to give the title compound.

Step 4:2-(4,4-difluoropiperidin-1-yl)-6-methyl-5-(2,2,2-trifluoroethoxy)nicotinonitrile

To a solution of2-(4,4-difluoropiperidin-1-yl)-3-iodo-6-methyl-5-(2,2,2-trifluoroethoxy)pyridine(0.20 g, 0.46 mmol) in DMA (3 mL) was added dicyanozinc (0.16 g, 1.4mmol), dppf (51 mg, 0.092 mmol) and Pd₂(dba)₃ (42 mg, 0.046 mmol). Themixture was degassed and backfilled with nitrogen three times. Then themixture was stirred at 130° C. for 1 h, diluted with water and extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (0-30% ethyl acetate/petroleumether) to give the title compound.

Step 5:2-(4,4-difluoropiperidin-1-yl)-6-methyl-5-(2,2,2-trifluoroethoxy)nicotinamide

To a solution of2-(4,4-difluoropiperidin-1-yl)-6-methyl-5-(2,2,2-trifluoroethoxy)nicotinonitrile(0.10 g, 0.30 mmol) and KOH (84 mg, 1.5 mmol) in DMSO (3 mL) was addedH₂O₂ (0.52 mL, 6.0 mmol). The mixture was stirred at 20° C. for 1 h. Themixture was diluted with Na₂SO₃ and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to a residue that was purified by silica gel chromatography(petroleum ether:EtOAc=1:1) to give the title compound.

Step 6:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-5-(2,2,2-trifluoroethoxy)nicotinamide

To a solution of2-(4,4-difluoropiperidin-1-yl)-6-methyl-5-(2,2,2-trifluoroethoxy)nicotinamide(60 mg, 0.17 mmol) in dioxane (1.5 mL) was added Cs₂CO₃ (0.17 g, 0.51mmol), 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (0.14g, 0.26 mmol) and XantPhos-Pd-G2 (15 mg, 0.017 mmol). The mixture wasdegassed and backfilled with nitrogen three times. The mixture wasstirred at 100° C. for 13 h. The solution was washed with water andextracted with EtOAc. The organic layer was dried over Na₂SO₄, filteredand concentrated to a residue was purified by silica gel chromatography(petroleum ether:EtOAc=1:1) to give the title compound.

Step 7:2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(2,2,2-trifluoroethoxy)nicotinamide(183)

A solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-5-(2,2,2-trifluoroethoxy)nicotinamide(0.12 g, 0.15 mmol) in TFA (1 mL) and dichloromethane (3 mL) was stirredat 20° C. for 1 h. The mixture was concentrated under reduced pressureto give a residue that was purified by by reverse phase chromatography(41-100% MeCN in water with 0.1% TFA, C18 column). LRMS m/z (M+H):calculated 510.1, observed 510.1. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.58(d, J=5.6 Hz, 1H), 8.47 (d, J=1.6 Hz, 1H), 7.84 (dd, J=2.0, 5.6 Hz, 1H),7.81 (s, 1H), 4.63 (q, J=8.4 Hz, 2H), 3.33-3.40 (m, 4H), 2.46 (s, 3H),2.04-2.16 (m, 4H).

Example 1842-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1: 4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane

To a solution of1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane(Intermediate 38, 1.8 g, 5.7 mmol) in dioxane (20 mL) and water (5 mL)were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.7 mL, 11mmol), K₂CO₃ (1.6 g, 11 mmol) and PdCl₂(dppf) (0.42 g, 0.57 mmol). Themixture was stirred at 100° C. for 10 hours under a nitrogen atmosphere.Then the mixture was diluted with water and extracted with EtOAc. Theorganic phase was washed with brine, dried over Na₂SO₄, and filtered,concentrated to give a residue that was purified by silica gelchromatography (4% ethyl acetate/PE) to give the title compound.

Step 2:1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane

To a solution of4,4-difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azepane (1.2 g,4.1 mmol) in DMF (10 mL) was added NBS (1.1 g, 6.1 mmol) dropwise withstirring at 20° C. The mixture was stirred at 20° C. for 10 hours, thendiluted in EtOAc and water. The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue that was purified by silica gel chromatography (3%EtOAc/petroleum ether) to give the title compound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide

A mixture of1-(3-bromo-6-methyl-5-(trifluoro-methyl)pyridin-2-yl)-4,4-difluoroazepane(0.30 g, 0.80 mmol),4-amino-N,N-bis(2,4-dimethoxy-benzyl)pyridine-2-sulfonamide (0.76 g, 1.6mmol), DMAP (9.8 mg, 0.080 mmol) and tBu₃—Pd-G2 (41 mg, 0.080 mmol) wastaken up in DMF (10 mL) and sparged with nitrogen for 10 min. Then Et₃N(0.56 mL, 4.0 mmol) was added. The reaction vial was loaded into a parreactor and degassed three times with nitrogen (N₂/vent), followed bythree times with carbon monoxide ((120 psi CO)/vent). The mixture wasleft exposed to 120 psi of CO and heated to 120° C. for 12 hours. Thenthe mixture was filtered, and the filtrate was diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue thatwas purified by silica gel chromatography (petroleum ether/ethylacetate=1/1) to give the title compound.

Step 4:2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide

A solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(4,4-difluoroazepan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide(0.43 g, 0.43 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at 20° C.for 1 hour. Then the mixture was filtered and the filtrate was dilutedwith water and extracted with EtOAc. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to give aresidue that was purified by silica gel chromatography (DCM/MeOH=20/1)to give the title compound. LRMS m/z (M+H): calculated 494.1, observed494.1. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56 (d, J=5.4 Hz, 1H), 8.38 (d,J=1.8 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.86-7.88 (m, 1H), 7.69 (d, J=2.7Hz, 1H), 6.50-6.97 (m, 1H), 3.66-3.74 (m, 2H), 3.42 (t, J=5.6 Hz, 2H),2.24-2.39 (m, 2H), 1.85-2.02 (m, 4H).

Example 1856-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

Step 1:1-(6-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane

To a solution of1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane(Intermediate 38, 0.70 g, 2.2 mmol) in dioxane (10 mL) and water (2 mL)were added potassium cyclopropyltri-fluoroborate (0.66 g, 4.4 mmol),K₂CO₃ (0.62 g, 4.4 mmol) and PdCl₂(dppf) (0.16 g, 0.22 mmol). Themixture was stirred at 100° C. for 10 hours under nitrogen, then dilutedwith water and extracted with EtOAc. The organic phase was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated to givea residue that was purified by silica gel chromatography (5% ethylacetate/PE) to give the title compound.

Step 2:1-(3-bromo-6-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane

To a solution of1-(6-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane(0.30 g, 0.94 mmol) in DMF (3 mL) was added NBS (0.25 g, 1.4 mmol) withstirring at 20° C. The mixture was stirred at 20° C. for 10 hours, thenextracted with EtOAc and water. The organic layer was separated, washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate=5/1) to give the titlecompound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamide

1-(3-bromo-6-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazepane(70 mg, 0.140 mmol),4-amino-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (80 mg, 0.17mmol), DMAP (1.7 mg, 0.014 mmol), and P(tBu)₃—Pd-G2 (7.2 mg, 0.014 mmol)were taken up in DMF (3 mL). The mixture was degassed with nitrogen for10 minutes, then triethylamine (43 mg, 0.42 mmol) was added. Thereaction vial was degassed (3×N₂/vent), then (3×CO (120 psi)/vent), andthen left exposed to 120 psi of CO and heated to 120° C. for 12 h. Thenthe reaction mixture was filtered and the filtrate was diluted withwater and extracted with EtOAc. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated togive a residue that was purified by silica gel chromatography (petroleumether/ethyl acetate=1/1) to give the title compound.

Step 4:6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide

A solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)-sulfamoyl)pyridin-4-yl)-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)-nicotinamide(60 mg, 0.073 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at 20° C.for 1 hour. Then the mixture was concentrated under reduced pressure andpurified by reverse phase chromatography (50-100% MeCN in water with0.1% TFA, C18 column) to give the title compound. LRMS m/z (M+H):calculated 520.1, observed 519.9. ¹H NMR δ (ppm) (400 MHz, CD₃OD): 8.56(d, J=5.6 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 7.86-7.88 (m,1H), 3.67-3.77 (m, 2H), 3.42 (t, J=5.6 Hz, 2H), 2.21-2.36 (m, 3H),1.86-2.00 (m, 4H), 1.15-1.19 (m, 2H), 1.01-1.09 (m, 2H).

Example 1862-(azepan-1-yl)-N-(5-fluoropyridin-3-yl)-5-(trifluoromethyl)nicotinamide

To a mixture of 2-(azepan-1-yl)-5-(trifluoromethyl)nicotinic acid(Intermediate 17, 10 mg, 0.035 mmol) in pyridine (0.3 mL) was added3-amino-5-fluoropyridine (11 mg, 0.10 mmol) and EDC (10 mg, 0.052 mmol).The mixture was sonicated and stirred at ambient temperature 16 hours ina sealed vial. Then the mixture was concentrated under a stream ofnitrogen, followed by high vacuum. The resulting residue was purified byreverse phase chromatography (30-100% MeCN in water with 0.1% TFA, C18column) to give the title compound. LRMS m/z (M+H): calculated 383.1,observed 383.1. ¹H NMR δ (ppm) (500 MHz, DMSO-d₄) □ 11.04 (s, 1H), 8.65(s, 1H), 8.53 (m, 1H), 8.35 (d, 1H), 8.12 (dt, 1H), 8.02 (d, 1H), 3.34(s, 4H), 1.75 (m, 4H), 1.45 (m, 4H).

TABLE 8 The compounds of Exmples 187-200 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 186.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ 187

2-(azepan-1-yl)-5- chloro-N-(2-methoxy- 4-pyridyl)-4,6-dimethyl-pyridine-3- carboxamide 389.2 389.2 188

2-(azepan-1-yl)-5- chloro-4,6-dimethyl-N- (5-sulfamoyl-3-pyridyl)pyridine-3- carboxamide 438.1 438.1 189

5-chloro-2-(4,4- difluoro-1-piperidyl)- 4,6-dimethyl-N-(5- sulfamoyl-3-pyridyl)pyridine-3- carboxamide 460.1 460.1 190

2-(6- azaspiro[2.5]octan-6- yl)-5-chloro-4,6- dimethyl-N-(5-sulfamoyl-3- pyridyl)pyridine-3- carboxamide 450.1 450.2 191

5-chloro-4,6-dimethyl- 2-(1-piperidyl)-N-(5- sulfamoyl-3-pyridyl)pyridine-3- carboxamide 424.1 424.1 192

2-(4,4-difluoroazepan- 1-yl)-6-methoxy-N-(5- sulfamoyl-3-pyridyl)pyridine-3- carboxamide 442.1 442.1 193

2-(azepan-1-yl)-N-(5- cyano-3-pyridyl)-5- (trifluoromethyl)- pyridine-3-carboxamide 390.1 390.1 194

2-(azepan-1-yl)-N-(5- methoxy-3-pyridyl)-5- (trifluoromethyl)-pyridine-3- carboxamide 395.2 395.2 195

2-(azepan-1-yl)-N-(5- methyl-3-pyridyl)-5- (tri-fluoromethyl)-pyridine-3- carboxamide 379.2 379.2 196

2-(azepan-1-yl)-N-[5- (hydroxymethyl)-3- pyridyl]-5-(trifluoro-methyl)pyridine-3- carboxamide 395.2 395.2 197

2-(azepan-1-yl)-N-(2- cyano-4-pyridyl)-5- (tri- fluoromethyl)pyridine-3-carboxamide 390.2 390.4 198

2-(azepan-1-yl)-N-(2- ethylsulfonyl-4- pyridyl)-5-(trifluoro-methyl)pyridine-3- carboxamide 457.1 457.4 199

2-(azepan-1-yl)-N-(3- bromoimidazo[1,2- a]pyridin-6-yl)-5-(trifluoromethyl)- pyridine-3- carboxamide 482.1 482.2 200

2-(azepan-1-yl)-5- (trifluoromethyl)-N-[5- (trifluoromethyl)-3-pyridyl]pyridine-3- carboxamide 433.1 433.3

Example 2012-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2-(azepan-1-yl)-5-chloro-4,6-dimethylnicotinic acid

To a solution of 2,5-dichloro-4,6-dimethylnicotinic acid (0.50 g, 2.3mmol) in DMF (5 mL) was added DIPEA (2.0 mL, 11 mmol), K₂CO₃ (2.0 g) andhexamethyleneimine (1.1 g, 11 mmol). The reaction vial was sealed andheated at 140° C. for 16 hours. Then the reaction mixture was cooled tort and diluted in EtOAc. The organic layer was washed with 5% AcOH inwater, brine, dried over MgSO₄, filtered and concentrated to give aresidue that was purified via silica gel chromatography (0-75%EtOAc/hexanes) to give the title compound.

Step 2:2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution of 2-(azepan-1-yl)-5-chloro-4,6-dimethylnicotinic acid (35mg, 0.12 mmol) in pyridine (1 mL) was added EDC (36 mg, 0.19 mmol) and4-aminopyridine-2-sulfonamide (54 mg, 0.31 mmol). The mixture wasstirred at 80° C. for 16 h, then concentrated under reduced pressure togive a residue that was purified reverse phase chromatography (5-95%MeCN in water with 0.1% TFA, C18 column) to give the title compound.LRMS m/z (M+H): calculated 438.1, observed 438.5. ¹H NMR δ (ppm) (600MHz, CD₃OD): 8.57 (d, J=5.5 Hz, 4H), 8.36 (d, J=1.6 Hz, 4H), 7.84 (dd,J=5.5, 1.9 Hz, 4H), 3.58-3.53 (m, 18H), 2.49 (s, 13H), 2.33 (s, 13H),1.93 (s, 1H), 1.75 (s, 15H), 1.52 (s, 16H).

Example 2025-chloro-4,6-dimethyl-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2-(azepan-1-yl)-5-chloro-4,6-dimethylnicotinic acid

To a mixture of 2,5-dichloro-4,6-dimethylnicotinic acid (0.50 g, 2.3mmol) and K₂CO₃ (0.31 g, 2.3 mmol) in a vial was added DMF andhexamethyleneimine (0.56 g, 5.7 mmol). The vial was sealed and stirredat 135° C. for 16 h, then the mixture was dissolved in EtOAc. Theorganic layer was washed with 5% AcOH in water, brine, dried over MgSO₄,filtered and concentrated under reduced pressure to give a residue thatwas purified by silica gel chromatography (20% EtOAc/hexanes) to givethe title compound.

Step 2:5-chloro-4,6-dimethyl-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution of5-chloro-4,6-dimethyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (35mg, 0.12 mmol) in pyridine (1 mL) was added EDC (34 mg, 0.18 mmol) and4-aminopyridine-2-sulfonamide (51 mg, 0.30 mmol). The mixture wasstirred at 80° C. for 16 h, then concentrated and purified by reversephase chromatography (5-95% MeCN in water with 0.1% TFA, C18 column) togive the title compound. LRMS m/z (M+H): calculated 450.1, observed450.4. ¹H NMR δ (ppm) (600 MHz, CD₃OD): 8.58 (d, J=5.3 Hz, 3H), 8.40 (s,3H), 7.84 (d, J=5.3 Hz, 3H), 3.36-3.31 (m, 14H), 2.54 (s, 10H), 2.38 (s,9H), 1.93 (s, 1H), 1.36-1.31 (m, 12H), 0.28 (s, 11H).

Example 2034-(2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide

Step 1:2-(azepan-1-yl)-N-(2-cyanopyridin-4-yl)-5-(trifluoromethyl)nicotinamide

The title compound was synthesized according to the synthetic procedurefor Example 202 starting from Intermediate 17.

Step 2: 4-(2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide

A mixture of2-(azepan-1-yl)-3-((2-cyanopyridin-4-yl)carbamoyl)-5-(trifluoromethyl)pyridin-1-ium2,2,2-trifluoroacetate (11 mg, 0.021 mmol) and NaOH (7.2 μl, 0.043 mmol)in MeOH (500 μl) was heated to 80° C. for 1 hour. Then the mixture wasconcentrated under reduced pressure and purified by reverse phasechromatography (5-9% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 408.2, observed 408.4. ¹HNMR δ (ppm) (600 MHz, CD₃OD): 8.60 (d, J=5.7 Hz, 2H), 8.54 (s, 2H), 8.47(s, 2H), 8.06 (d, J=5.9 Hz, 2H), 8.02 (s, 2H), 4.09 (s, 1H), 3.58 (q,J=8.5, 7.0 Hz, 10H), 3.30 (s, 24H), 1.83 (s, 8H), 1.53 (s, 9H).

Example 2045-bromo-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

The title compound was synthesized according to the synthetic procedurefor Example 203 starting from 2-chloro-5-bromo-nicotinic acid. LRMS m/z(M, M+2): calculated 476.0/478.0, observed 476.2/478.2.

Example 2052-(4,4-difluoropiperidin-1-yl)-5-phenyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: tert-butyltert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-phenylnicotinamido)pyridin-2-yl)sulfonyl)carbamate

A mixture of phenylboronic acid (14 mg, 0.12 mmol), tert-butyl((4-(5-bromo-2-(4,4-difluoropiperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)(tert-butyl)carbamate(Intermediate 39, 50 mg, 0.08 mmol), potassium phosphate tribasic (50mg, 0.24 mmol), and Xphos Pd G2 (6.2 mg, 0.0079 mmol) was suspended inTHF (0.80 mL). The reaction vessel was sealed and degassed via vacuumand purged with nitrogen (5×). The reaction mixture was stirred at 60°C. for 5 h, then filtered through a pad of Celite™, rinsed with ethylacetate and concentrated to give the title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-5-phenyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution of crude tert-butyltert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-phenylnicotinamido)-pyridin-2-yl)sulfonyl)carbamate(50 mg, 0.079 mmol), in DCM (0.8 mL) at 0° C. was added TFA (0.31 mL,4.0 mmol). The mixture was stirred at rt for 1.5 h and then concentratedby blowing air over the mixture. The residue was purified by reversephase chromatography (5-95% MeCN in water with 0.1% TFA, C18 column) togive the title compound. LRMS m/z (M+H): calculated 474.1, observed474.4.

Example 2062-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: tert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

A mixture of tert-butyl((4-(5-bromo-2-(4,4-difluoropiperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)(tert-butyl)carbamate(Intermediate 39, 50 mg, 0.08 mmol), cesium carbonate (0.13 g, 0.40mmol), and Ruphos Pd G2 (12 mg, 0.016 mmol) was suspended in dioxane(0.80 mL). Then piperidine (23 uL, 0.24 mmol) was added and the reactionvessel was sealed and degassed via vacuum and purged with N₂ (5×). Thereaction mixture was stirred at 80° C. for 5 h then 100° C. for 15 h,then filtered through a pad of Celite™, rinsed with ethyl acetate, andconcentrated to give the title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution of tert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(46 mg, 0.079 mmol), in DCM (0.8 mL) at 0° C. was added TFA (0.30 mL,4.0 mmol). The mixture was stirred at rt for 2 h then concentrated byblowing air over top. The residue was purified by reverse phasechromatography (5-95% MeCN in water with 0.1% TFA, C18 column) to givethe title compound. LRMS m/z (M+H): calculated 481.2, observed 481.5.

Example 2072-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: tert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate

A mixture of 1H-pyrazole (16 mg, 0.24 mmol), tert-butyl((4-(5-bromo-2-(4,4-difluoropiperidin-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)(tert-butyl)carbamate(Intermediate 39, 50 mg, 0.08 mmol), cesium carbonate (51 mg, 0.16mmol), and copper (I) iodide (12 mg, 0.063 mmol) was suspended in DMSO(0.80 mL). Then (1R, 2R)—N,N′-dimethyl-1,2-cyclohexanediamine (12 uL,0.079 mmol) was added and the reaction vessel was sealed and degassedvia vacuum and purged with nitrogen (5×). The reaction mixture wasstirred at 120° C. for 5 h, then partitioned between water and ethylacetate. The organic layer was separated and washed with water, driedover Na₂SO₄, filtered, and concentrated to give the title compound.

Step 2:2-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide

To a solution of crude tert-butyl((4-(2-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)nicotinamido)pyridin-2-yl)sulfonyl)carbamate(44 mg, 0.079 mmol) in DCM (0.8 mL) at 0° C. was added TFA (0.30 mL, 4.0mmol). The mixture was stirred at rt for 2 h and then concentrated byblowing air over top. The resulting residue was purified by reversephase chromatography (5-95% MeCN in water with 0.1% TFA, C18 column) togive the title compound. LRMS m/z (M+H): calculated 464.1, observed464.4.

Example 208N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamide

To a mixture ofN-(2-methoxypyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)-nicotinamide(Example 143, 131 mg, 0.322 mmol) in DMF (0.3 mL) was added pyridinehydrochloride (0.19 g, 1.6 mmol) and the resulting mixture was heated at105° C. in a sealed vial for 16 h. Additional pyridine hydrochloride(250 mg) was added and the mixture was heated at 105° C. for 3 hours.The mixture was then diluted with EtOAc, washed with saturated aqueousNaHCO₃, water, brine, dried over MgSO₄ and concentrated to give aresidue. The residue was swished with CHCl₃ and filtered to give thetitle compound. LRMS m/z (M+H): calculated 393.2, observed 393.1. ¹H NMRδ (ppm) (500 MHz, DMSO-d₄) □ 11.26 (s, 1H), 10.56 (s, 1H), 8.56 (m, 1H),7.97 (d, 1H), 7.33 (d, 1H), 6.79 (s, 1H), 6.41 (s, 1H), 3.52 (m, 4H),1.38 (m, 4H), 0.33 (s, 4H).

TABLE 9 The compounds of Exmples 209-213 were prepared according to asynthetic procedure similar to the synthetic procedure for Example 208.Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺ 209

5-chloro-4,6-dimethyl- N-(2-oxo-1,2- dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6- yl)nicotinamide 387.2 387.2 210

2-(4,4-difluoroazepan-1- yl)-N-(2-oxo-1,2- dihydropyridin-4-yl)-5-(trifluoromethyl)- nicotinamide 417.1 417.1 211

5-chloro-4,6-dimethyl- N-(2-oxo-1,2- dihydropyridin-4-yl)-2-(piperidin-1-yl)- nicotinamide 361.1 361.2 212

2-(azepan-1-yl)-N-(2- oxo-1,2-dihydropyridin- 4-yl)-5-(trifluoro-methyl)nicotinamide 381.1 381.2 213

2-(azepan-1-yl)-5- chloro-4,6-dimethyl-N- (2-oxo-1,2- dihydropyridin-4-yl)nicotinamide 375.2 375.2

Example 2145-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

Step 1: 2,5-dichloro-N,4,6-trimethylnicotinamide

A mixture of 2,5-dichloro-4,6-dimethylnicotinic acid (150 mg, 0.68 mmol)in SOCl₂ (2.0 mL, 27 mmol) was stirred at room temperature for 1 hourunder a nitrogen atmosphere. The mixture was evaporated under reducedpressure, and the resulting residue was dissolved in THF (2 mL). Thesolution was added dropwise into a solution of methanamine (2.0 mL, 0.68mmol) in water at room temperature. The resultant mixture was purifiedby prep-TLC (petroleum ether:ethyl acetate 1:1) to give the titlecompound.

Step 2: 5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethylnicotinamide

To a mixture of 2,5-dichloro-N,4,6-trimethylnicotinamide (50 mg, 0.21mmol) and 4,4-difluoroazepane hydrochloride (Intermediate 40, 44 mg,0.26 mmol) in NMP (2 mL) was added DIPEA (0.11 mL, 0.64 mmol) at 25° C.The reaction mixture was stirred at 100° C. for 18 h, then additional4,4-difluoroazepane hydrochloride (20 mg, 0.12 mmol) was added, and thereaction mixture was stirred at 220° C. for 2 h in a microwave reactor.The mixture was cooled to room temperature, treated with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue that was purified by silica gelchromatography (petroleum ether:ethyl acetate 1:1) to give the titlecompound.

Step 3:N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethylnicotinamide

To a mixture of5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethylnicotinamide (40 mg,0.12 mmol) and4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (Intermediate4, 78 mg, 0.14 mmol) and Cs₂CO₃ (0.12 g, 0.36 mmol) in dioxane (3 mL)was added Xantphos G3 (11 mg, 0.012 mmol). The reaction mixture wasstirred at 100° C. for 18 h under an atmosphere of nitrogen. The mixturewas then treated with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue that was purifiedby silica gel chromatography (petroleum ether:ethyl acetate 1:1) to givethe title compound.

Step 4:5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a solution ofN-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethylnicotinamide(30 mg, 0.038 mmol) in DCM (1 mL) was added TFA (0.8 mL) with stirringat 25° C. The reaction mixture was stirred at 25° C. for 1 h. Then themixture was concentrated under reduced pressure and purified by reversephase chromatography (45-75% MeCN in water with 0.1% TFA, C18 column) togive the title compound. LRMS m/z (M+H): calculated 488.1, observed488.2. ¹H NMR δ (500 MHz, CD₃OD): 8.46 (d, J=5.0 Hz, 1H), 7.44 (d, J=1.5Hz, 1H), 7.11 (dd, J=2.0, 5.0 Hz, 1H), 3.54 (s, 3H), 3.41-3.47 (m, 1H),3.22-3.29 (m, 1H), 3.14-3.21 (m, 1H), 3.05-3.14 (m, 1H), 2.44 (s, 3H),2.39 (s, 3H), 1.74-2.15 (m, 6H).

Example 2155-chloro-4,6-dimethyl-2-(4-methylcyclohexyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a vial was added nickel(II) iodide (17 mg, 0.053 mmol),pyridine-2,6-bis(carboximidamide) (13 mg, 0.053 mmol) and zinc (70 mg,1.1 mmol), and the vial was evacuated and backfilled with nitrogen. ThenDMA (1.0 mL) was added to the vial with stirring for 5 minutes at roomtemperature. A solution of2,5-dichloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide (100mg, 0.27 mmol), NaI (80 mg, 0.53 mmol) and 1-bromo-4-methylcyclohexane(94 mg, 0.53 mmol) in DMA (2 mL) was added to the vial containing theabove mixture. The reaction mixture was heated to 80° C. for 12 h, thenthe mixture was diluted with DMF (2 mL), filtered and purified byreverse phase chromatography (38-58% MeCN in water with 0.1% TFA, C18column) to give the title compound. LRMS m/z (M+H): calculated 437.1,observed 437.2. ¹H NMR δ (500 MHz, CD₃OD) 8.62 (d, J=5.5 Hz, 1H), 8.37(d, J=1.5 Hz, 1H), 7.82-7.90 (m, 1H), 2.67 (s, 3H), 2.64-2.66 (m, 1H),2.39 (s, 3H), 1.67-1.95 (m, 6H), 1.37-1.49 (m, 1H), 0.91-1.03 (m, 2H),0.89 (d, J=6.5 Hz, 3H).

Example 2165-chloro-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrazine-2-carboxamide

Step 1: 1-(6-chloro-3-iodopyrazin-2-yl)-4,4-difluoroazepane

To a mixture of 3,5-dichloro-2-iodopyrazine (4.0 g, 8.7 mmol) and CsF(4.0 g, 26 mmol) in DMSO (10 mL) was added 4,4-difluoroazepanehydrochloride (2.2 g, 13 mmol). The reaction mixture was stirred at 50°C. for 10 hours, then the solvent was removed under reduced pressure.The resulting residue was diluted with water, and extracted with EtOAc.The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue that was purified bysilica gel chromatography (petroleum ether/ethyl acetate 5/1) to givethe title compound.

Step 2: 1-(6-chloro-3-vinylpyrazin-2-yl)-4,4-difluoroazepane

To a solution of 1-(6-chloro-3-iodopyrazin-2-yl)-4,4-difluoroazepane(2.4 g, 6.4 mmol) in THF (20 mL) and water (5 mL) was added Cs₂CO₃ (6.3g, 19 mmol), Pd(dppf)Cl₂ (0.47 g, 0.64 mmol) and potassiumvinyltrifluoroborate (1.3 g, 9.6 mmol). The reaction mixture wasdegassed and backfilled with nitrogen (three times), then the reactionmixture was stirred at 55° C. for 13 hours. The mixture was filtered,diluted with water and extracted with EtOAc. The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue that was purified by silica gelchromatography (petroleum ether/ethyl acetate 10/1) to provide the titlecompound.

Step 3: 5-chloro-3-(4,4-difluoroazepan-1-yl)pyrazine-2-carbaldehyde

To a mixture of 1-(6-chloro-3-vinylpyrazin-2-yl)-4,4-difluoroazepane(1.2 g, 4.4 mmol) in THF (15 mL) and water (3 mL) was added4-methylmorpholine N-oxide (1.0 g, 8.8 mmol) and OsO₄ (0.014 mL, 0.044mmol). The reaction mixture was stirred at 20° C. for 12 hours, thenNaIO₄ (4.7 g, 22 mmol) was added. The reaction mixture was stirred at20° C. for an additional 2 hours. Then the mixture was diluted withwater and extracted with DCM. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue that was purified by silica gel chromatography (5%EtOAc/hexanes) to give the title compound.

Step 4: 5-chloro-3-(4,4-difluoroazepan-1-yl)pyrazine-2-carboxylic acid

To a stirred mixture of5-chloro-3-(4,4-difluoroazepan-1-yl)pyrazine-2-carbaldehyde (0.10 g,0.36 mmol), 2-methylbut-2-ene (0.10 g, 1.5 mmol) and NaH₂PO₄ (0.65 g,5.4 mmol) in tBuOH (3 mL) and water (2 mL) was added in one portionNaClO₂ (0.20 g, 2.2 mmol) at 0° C. The reaction mixture was stirred at20° C. for 12 hours. The organic layer was freeze-dried to give thetitle compound.

Step 5: tert-butyltert-butyl((4-(5-chloro-3-(4,4-difluoroazepan-1-yl)pyrazine-2-carboxamido)pyridin-2-yl)sulfonyl)carbamate

To a solution of5-chloro-3-(4,4-difluoroazepan-1-yl)pyrazine-2-carboxylic acid (100 mgcrude) and tert-butyl((4-aminopyridin-2-yl)sulfonyl)(tert-butyl)carbamate (Intermediate 8,0.17 g, 0.51 mmol) in pridine (2 mL) was added POCl₃ (0.064 mL, 0.69mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Themixture was concentrated under reduced pressure to a residue that wasdiluted with water and extracted with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue that was purified by silica gel chromatography (50%petroleum ether/EtOAc) to give the title compound.

Step 6:5-chloro-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrazine-2-carboxamide

A solution of tert-butyltert-butyl((4-(5-chloro-3-(4,4-difluoroazepan-1-yl)pyrazine-2-carboxamido)pyridin-2-yl)sulfonyl)carbamate(0.19 g, 0.25 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at 20° C.for 2 hours. Then the reaction mixture was concentrated under reducedpressure. The resulting residue was dissolved in DMF and purified byreverse phase chromatography (39-59% MeCN in water with 0.1% TFA, C18column) to give the title compound. LRMS m/z (M+H): calculated 447.1,observed 447.1. ¹H NMR δ (500 MHz, CD₃OD) 8.57 (d, J=5.5 Hz, 1H), 8.47(d, J=2.0 Hz, 1H), 7.92-7.96 (m, 2H), 3.72-3.82 (m, 2H), 3.47 (t, J=5.5Hz, 2H), 2.29-2.40 (m, 2H), 1.91-2.07 (m, 4H).

Example 2175-chloro-2-cycloheptyl-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a vial was added nickel(II) iodide (17 mg, 0.053 mmol),pyridine-2,6-bis(carboximidamide) (13 mg, 0.053 mmol) and zinc (70 mg,1.1 mmol), and the vial was evacuated and backfilled with nitrogen. ThenDMA (1.0 mL) was added to the vial with stirring for 5 minutes at roomtemperature. A solution of2,5-dichloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide (100mg, 0.27 mmol), NaI (40 mg, 0.27 mmol) and bromocycloheptane (94 mg,0.53 mmol) in DMA (1.5 mL) was added to the vial containing the abovemixture. The reaction mixture was heated to 80° C. for 12 h, then themixture was diluted with DMF (2 mL), filtered and purified by reversephase chromatography (39-69% MeCN in water with 0.1% TFA, C18 column) togive the title compound. LRMS m/z (M+H): calculated 437.1, observed437.2. ¹H NMR δ (500 MHz, CD₃OD) 8.63 (d, J=5.5 Hz, 1H), 8.37 (d, J=1.5Hz, 1H), 7.87-7.88 (m, 1H), 2.82-2.90 (m, 1H), 2.65 (s, 3H), 2.40 (s,3H), 1.80-1.92 (m, 6H), 1.38-1.67 (m, 6H).

Example 2185-chloro-2-(4,4-difluorocyclohexyl)-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide

To a vial was added nickel(II) iodide (17 mg, 0.053 mmol),pyridine-2,6-bis(carboximidamide) (13 mg, 0.053 mmol) and zinc (70 mg,1.1 mmol), and the vial was evacuated and backfilled with nitrogen. ThenDMA (1.0 mL) was added to the vial with stirring for 5 minutes at roomtemperature. A solution of2,5-dichloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide (100mg, 0.27 mmol), NaI (40 mg, 0.27 mmol) and4-bromo-1,1-difluorocyclohexane (106 mg, 0.53 mmol) in DMA (1.5 mL) wasadded to the vial containing the above mixture. The reaction mixture washeated to 80° C. for 12 h, then the mixture was diluted with DMF (2 mL),filtered and purified by reverse phase chromatography (43-63% MeCN inwater with 0.1% TFA, C18 column) to give the title compound. LRMS m/z(M+H): calculated 459.1, observed 459.1. ¹H NMR δ (500 MHz, CD₃OD) 8.61(d, J=5.5 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 7.86-7.88 (m, 1H), 2.74-2.83(m, 1H), 2.63 (m, 3H), 2.38 (s, 3H), 2.07-2.23 (m, 4H), 1.75-1.96 (m,4H).

Example of a Pharmaceutical Composition

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of the Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

Biological Assays

Qube® Assay Experimental Procedure Compounds were tested on human Nav1.8and Nav1.5 channels stably expressed in human embryo kidney (HEK) 293cells. Sodium current measurements on Qube® were conducted as follows:automated 384-well patch-clamp assays on the Qube® platform (SophionBiosciences) were used to measure the inhibition of sodium flow throughhuman Na_(v)1.8 and Nav1.5 channels. Whole-cell voltage-clamp recordingswere performed in QChips® (Sophion Biosciences) at room temperature.Nav1.8 current measurements on Qube® were obtained as follows: Nav1.8currents were elicited with a 10 second 1 Hertz (Hz) pulse train from aholding potential of −90 millivolts (mV), delivered to the cells onceper minute in the control condition (DMSO only) and after compoundaddition. The 1 hertz pulse train stimulation consisted often testpulses to 10 millivolt (mV) for 20 milliseconds (ms), each of which wasfollowed by a 980 millisecond repolarization to −67 millivolts. At theend of the 10 second pulse train stimulation, a 5 secondhyperpolarization step to −100 millivolt (mV) was used to recover Nav1.8from fast inactivation. The peak currents elicited by the 1^(st) and10^(th) test pulses were used to determine IC₅₀ values for restinginhibition and inactivated state inhibition. Nav1.5 current measurementson Qube® were obtained as follows: Nav1.5 currents were elicited with a20 second 3 Hertz pulse train in the control condition (DMSO only) andafter compound addition. The pulse train consisted of sixty 20millisecond test pulses to 0 millivolt from a holding potential of −80millivolt (mV). The average peak currents elicited by the last 3 testpulses were used to determine IC₅₀ values for Nav1.5 inhibition.

The following buffers were used for the Qube® recordings: Externalbuffer for Nav1.8 Qube® recording: 150 NaCl, 2 CaCl₂, 5 KCl, 1 Mg Cl₂,10 HEPES, 12 Dextrose; External buffer for Qube® Nav1.5 recording: 120N-Methyl-D-Glucamine, 40 NaCl, 1 KCl, 2.7 CaCl₂), 5 HEPES, 0.5 MgCl₂;and Internal buffer for Qube® recording: 120 CsF, 30 CsCl, 10 EGTA, 5HEPES, 5 NaF, 2 MgCl₂.

For all Qube® experiments offline analysis was used to determine percentinhibition as a function of drug concentration. IC₅₀ values weredetermined by fitting to the Hill equation.

The compounds of the present invention have Na_(v)1.8 IC₅₀ values in theQube® Assay of less than 10 micromolar. Specific IC₅₀ values of thecompounds of Examples 1-218 in the Qube® Assay are listed in Table I.

TABLE I IC₅₀ values (nM) for Examples in the Na_(v) 1.8 Qube ® AssayExample IC₅₀ (nM) 1 406 2 2189 3 2377 4 5431 5 820 6 355 7 2827 8 2354 9816 10 174 11 212 12 94 13 4.1 14 45 15 6.5 16 12 17 3.1 18 0.9 19 1.620 67 21 4.5 22 3.0 23 2.6 24 2.1 25 5.4 26 1856 27 31 28 1303 29 31 304.0 31 4.1 32 4.3 33 35 34 50 35 74 36 147 37 1247 38 24 39 441 40 4.141 5.1 42 341 43 37 44 59 45 1793 46 1.0 47 3.9 48 12 49 1.4 50 14 516.6 52 2.8 53 0.8 54 2.1 55 1.4 56 9.1 57 31 58 10 59 116 60 14 61 15 62105 63 20 64 23 65 94 66 88 67 25 68 29 69 82 70 41 71 60 72 714 73 22574 319 75 233 76 389 77 2978 78 5077 79 21 80 31 81 39 82 54 83 114 84147 85 152 86 172 87 223 88 275 89 275 90 294 91 616 92 659 93 707 94745 95 1419 96 1621 97 1896 98 2366 99 2558 100 4629 101 3.9 102 27 103166 104 56 105 696 106 103 107 139 108 191 109 289 110 505 111 633 1128413 113 9332 114 95 115 1.6 116 32 117 18 118 54 119 30 120 2.9 121 58122 20 123 28 124 50 125 144 126 21 127 220 128 94 129 753 130 3877 1312.0 132 5.3 133 12 134 155 135 57 136 494 137 26 138 5.8 139 16 140 91141 245 142 29 143 1540 144 36 145 161 146 177 147 22 148 26 149 57 15077 151 89 152 155 153 310 154 84 155 60 156 58 157 82 158 41 159 1627160 9.2 161 63 162 22 163 10 164 3.3 165 2.1 166 13 167 52 168 17 1696.9 170 24 171 9.2 172 0.3 173 199 174 4.1 175 53 176 1094 177 2.8 17813 179 102 180 14 181 17 182 62 183 82 184 0.5 185 3.8 186 1288 187 141188 5.9 189 13 190 31 191 124 192 163 193 654 194 1555 195 2774 196 5186197 244 198 425 199 5071 200 9665 201 1.3 202 1.9 203 139 204 55 205 71206 363 207 1081 208 287 209 12 210 86 211 357 212 570 213 80 214 347215 6.6 216 80 217 3.2 218 2.4

The scope of the claims should not be limited by the preferredembodiments set forth in the examples, but should be given the broadestinterpretation consistent with the description as a whole.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the scope of the invention. For example,effective dosages other than the particular dosages as set forth hereinabove may be applicable as a consequence of variations in responsivenessof the mammal being treated for any of the indications with thecompounds of the invention indicated above. The specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compounds selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

What is claimed is:
 1. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein A is pyridine,wherein pyridine is unsubstituted or substituted with one to threesubstituents selected from R^(a); B is pyridine, wherein pyridine isunsubstituted or substituted with one to three substituents selectedfrom R^(b); R¹ is selected from the group consisting of: (1) —SO₃H, (2)—SO₂NH₂, (3) —SO₂C₁₋₆alkyl, (4) —SO₂NH—C₁₋₆alkyl, (5)—SO₂C₃₋₆cycloalkyl, (6) —C(O)NH₂, (7) —CO₂H, (8) —CN, (9) halogen, (10)—OH, (11) —OC₁₋₆alkyl, and (12) —C₁₋₆alkyl, wherein each alkyl, andcycloalkyl is unsubstituted or substituted with one substituent selectedfrom R^(d); R² is selected from the group consisting of: (1) hydrogen,and (2) —C₁₋₆alkyl; R³ is selected from the group consisting of: (1) amonocyclic, bicyclic or spirocyclic C₃₋₁₂cycloalkyl ring, and (2) amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains 1-4 heteroatoms independently selectedfrom N(R^(m))_(r), O, and S, wherein each cycloalkyl ring and eachcycloheteroalkyl ring may be fused to an aryl or heteroaryl, and whereineach cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstitutedor substituted with one to eight substitutents selected from R^(c); eachR^(a) is selected from the group consisting of: (1) —C₁₋₆alkyl, (2)—OC₁₋₆alkyl, (3) halogen, (4) —OH, (5) oxo, (6) —CN, (7)—C₃₋₆cycloalkyl, and (8) —C₂₋₅cycloheteroalkyl, wherein each alkyl,cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with oneto six substituents selected from halogen, OH, NH₂, NH(C₁₋₆alkyl) andN(C₁₋₆alkyl)₂; each R^(b) is independently selected from the groupconsisting of: (1) —CF₃, (2) —CHF₂, (3) —OCHF₂, (4) —OCH₂CF₃, (5) —OCF₃,(6) CN, (7) F, (8) Cl, (9) Br, (10) —CH₃, (11) —C(CH₃)₃, (12) —OCH₃,(13) cyclopropyl, (14) cyclobutyl, (15) piperidine, (16)—CH₂-cyclopropyl, (17) —C₂alkynyl-cyclopropyl, and (18) pyrazole,wherein each R^(b) is unsubstituted or substituted with one to fivesubstituents selected from R^(f;) each R^(c) is independently selectedfrom the group consisting of: (1) —CF₃, (2) —CH₂CF₃, (3) —CHF₂, (4)—OCHF₂, (5) —OCF₃, (6) CN, (7) oxo, (8) —OH, (9) halogen, (10)—C₁₋₆alkyl, (11) —C₂₋₆alkenyl, (12) —C₂₋₆alkynyl, (13) —C₃₋₆cycloalkyl,(14) —C₂₋₆cycloheteroalkyl, (15) —C₁₋₆alkyl-C₃₋₆cycloalkyl, (16)—C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (17) —C₁₋₆alkyl-aryl, (18)—C₁₋₆alkyl-heteroaryl, (19) —C₁₋₆alkenyl-C₃₋₆cycloalkyl, (20)—C₁₋₆alkenyl-aryl, (21) —C₁₋₆alkenyl heteroaryl, (22)—C₁₋₆alkenyl-C₂₋₆cycloheteroalkyl, (23) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,(24) —C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl, (25) —C₂₋₆alkynyl-aryl, (26)—C₂₋₆alkynyl heteroaryl, (27) —OC₁₋₆alkyl, (28) —OC₂₋₆ alkenyl, (29)—OC₂₋₆ alkynyl, (30) —OC₃₋₆ cycloalkyl, (31) —OC₂₋₆ heterocycloalkyl,(32) —O-aryl, (33) —O-heteroaryl, (34) —OC₁₋₆alkyl-cycloalkyl, (35)—OC₁₋₆alkyl-cycloheteroalkyl, (36) —OC₁₋₆alkyl-aryl, (37) —OC₁₋₆alkyl-heteroaryl, (38) —S(O)_(m)R^(L), (39) —S(O)R^(L), (40) —S—R^(L),(41) —C₁₋₆alkyl-S(O)_(m)RL, (42) —C(O)R^(L), (43) —C(O)C₁₋₆alkyl-R^(L),(44) —OC(O)R^(L), (45) —CO₂R^(L), (46) aryl, and (47) heteroaryl,wherein each R^(c) is unsubstituted or substituted with one to fivesubstituents selected from R^(g;) R^(d) is independently selected fromthe group consisting of: (1) hydrogen, (2) halogen, (3) OH, (4) oxo, (5)—C₁₋₆alkyl, (6) —OC₁₋₆alkyl, (7) NH₂, (8) NH(C₁₋₆alkyl), and (9)N(C₁₋₆alkyl)₂; each R^(e) is independently selected from the groupconsisting of: (1) hydrogen, and (2) —C₁₋₆alkyl; each R^(f) is selectedfrom the group consisting of: (1) halogen, F (2) —C₁₋₆alkyl, (3) —OH,(4) —OC₁₋₆alkyl, (5) —OC₃₋₆cycloalkyl, (6) —OC₂₋₆cycloheteroalkyl, (7)CN, (8) —NH₂, (9) —NH(C₁₋₆alkyl), (10) —NH(C₃₋₆cycloalkyl), (11)—NH(C₂₋₆cycloheteroalkyl), (12) —N(C₁₋₆alkyl)₂, (13)—N(C₃₋₆cycloalkyl)₂, and (14) —N(C₂₋₆cycloheteroalkyl)₂, wherein eachalkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substitutedwith one to three substituents independently selected from: —OH,halogen, cyano, and —S(O)₂CH₃; each R^(g) is selected from the groupconsisting of: (1) halogen, (2) C₁₋₆alkyl, (3) —OH, (4) —OC₁₋₆alkyl, (5)—S(O)_(m)—C₁₋₆alkyl, (6) —CN, (7) —CF₃, (8) —OCHF₂, and (9) —OCF₃,wherein each alkyl is unsubstituted or substituted with one to threesubstituents independently selected from: —OH, halogen, cyano, and—S(O)₂CH₃; each R^(h) is independently selected from the groupconsisting of: (1) hydrogen, and (2) —C₁₋₆alkyl; each R^(i) isindependently selected from the group consisting of: (1) hydrogen, and(2) —C₁₋₆alkyl; each R^(j) is selected from the group consisting of: (1)—C₁₋₆alkyl, (2) —C₂₋₆alkenyl, (3) —C₃₋₆cycloalkyl, (4)—C₂₋₆cycloheteroalkyl, (5) aryl, and (6) heteroaryl, wherein each alkyl,alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH_(3;) eachR^(k) is selected from the group consisting of: (1) —C₁₋₆alkyl, (2)—C₂₋₆alkenyl, (3) —C₃₋₆cycloalkyl, (4) —C₃₋₆cycloalkyl, (5)—C₂₋₆cycloheteroalkyl, (6) aryl, and (7) heteroaryl, wherein each alkyl,alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl isunsubstituted or substituted with one to three substituentsindependently selected from: —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —OH,—OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and —S(O)₂CH_(3;) eachR^(L) is selected from the group consisting of: (1) —C₁₋₆alkyl, (2)—C₂₋₆alkenyl, (3) —C₃₋₆cycloalkyl, (4) —C₂₋₆cycloheteroalkyl, (5) aryl,and (6) heteroaryl, wherein each alkyl, alkenyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substitutedwith one to three substituents independently selected from: —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, halogen, cyano, and—S(O)₂CH_(3;) each R^(m) is independently selected from the groupconsisting of: (1) hydrogen, and (2) —C₁₋₆alkyl; each n is independently0, 1, 2, 3 or 4; each m is independently 0, 1 or 2; each p isindependently 0, 1, 2, 3 or 4; each q is independently 0 or 1; and eachr is independently 0 or
 1. 2. The compound according to claim 1 whereinR² is hydrogen; or a pharmaceutically acceptable salt thereof.
 3. Thecompound according to claim 1 wherein R¹ is selected from the groupconsisting of: (1) —SO₂NH₂, (2) —C(O)NH₂, and (3) —OH; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1 wherein R³ is selected from the group consisting of: amonocyclic, bicyclic or spirocyclic C₃₋₈cycloalkyl ring, and amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains 1-4 heteroatoms independently selectedfrom N(R^(m))_(r), O, and S, and wherein each cycloalkyl andcycloheteroalkyl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c); or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 1 wherein R³ is amonocyclic, bicyclic or spirocyclic C₂₋₁₂cycloheteroalkyl ring, whereinthe cycloheteroalkyl contains a nitrogen and 0-3 heteroatomsindependently selected from N(R^(m))_(r), O, and S, and wherein eachcycloheteroalkyl is unsubstituted or substituted with one to eightsubstitutents selected from R^(c); or a pharmaceutically acceptable saltthereof.
 6. The compound according to claim 1 wherein R³ is selectedfrom the group consisting of: (1) cyclohexane, (2) cycloheptane, (3)pyrrolidine, (4) azetidine, (5) piperidine, (6) piperazine, (7) azepane,(8) morpholine, (9) thiomorpholine, (10) oxazepane, (11) isoindoline,(12) dihydroisoquinoline, (13) azabicyclo[2.2.1]heptane, (14)azabicyclo[3.1.1]heptane, (15) azabicyclo[4.1.0]heptane, (16)azabicyclo[3.2.1]octane, (17) azabicyclo[3.2.0]heptane, (18)azaspiro[2.5]octane, (19) dihydrothieno[3,2-c]pyridine, (20)dihydroimidazo[1,2-a]pyrazine, and (21) hexahydrofuro[3,2-b]pyrrole,wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c;) or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 1 wherein R³ is selectedfrom the group consisting of: (1) pyrrolidine, (2) azetidine, (3)piperidine, (4) piperazine, (5) azepane, (6) morpholine, (7)thiomorpholine, (8) oxazepane, (9) isoindoline, (10)dihydroisoquinoline, (11) azabicyclo[2.2.1]heptane, (12)azabicyclo[3.1.1]heptane, (13) azabicyclo[4.1.0]heptane, (14)azabicyclo[3.2.1]octane, (15) azabicyclo[3.2.0]heptane, (16)azaspiro[2.5]octane, (17) dihydrothieno[3,2-c]pyridine, (18)dihydroimidazo[1,2-a]pyrazine, and (19) hexahydrofuro[3,2-b]pyrrole,wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c); or a pharmaceutically acceptable saltthereof.
 8. The compound according to claim 1 wherein R³ is selectedfrom the group consisting of: (1) piperidine, (2) azepane, and (3)morpholine, wherein R³ is unsubstituted or substituted with one to sixsubstituents selected from R^(c;) or a pharmaceutically acceptable saltthereof.
 9. The compound according to claim 1 wherein A is pyridine,wherein pyridine is unsubstituted or substituted with one to threesubstituents selected from R^(a;) B is pyridine, wherein pyridine isunsubstituted or substituted with one to three substituents selectedfrom R^(b;) R¹ is selected from the group consisting of: (1) —SO₃H, (2)—SO₂NH₂, (3) —SO₂C₁₋₆alkyl, (4) —SO₂NH—C₁₋₆alkyl, (5)—SO₂C₃₋₆cycloalkyl, (6) —C(O)NH₂, (7) —CO₂H, (8) —CN, (9) halogen, (10)—OH, (11) —OC₁₋₆alkyl, and (12) —C₁₋₆alkyl, wherein each alkyl, andcycloalkyl is unsubstituted or substituted with one substituent selectedfrom R^(d); R² is hydrogen; R³ is selected from the group consisting of:(1) pyrrolidine, (2) azetidine, (3) piperidine, (4) piperazine, (5)azepane, (6) morpholine, (7) thiomorpholine, (8) oxazepane, (9)isoindoline, (10) dihydroisoquinoline, (11) azabicyclo[2.2.1]heptane,(12) azabicyclo[3.1.1]heptane, (13) azabicyclo[4.1.0]heptane, (14)azabicyclo[3.2.1]octane, (15) azabicyclo[3.2.0]heptane, (16)azaspiro[2.5]octane, (17) dihydrothieno[3,2-c]pyridine, (18)dihydroimidazo[1,2-a]pyrazine, and (19) hexahydrofuro[3,2-b]pyrrole,wherein R³ is unsubstituted or substituted with one to eightsubstituents selected from R^(c;) or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 1 wherein A is pyridine,wherein pyridine is unsubstituted or substituted with one to threesubstituents selected from R^(a) B is pyridine, wherein pyridine isunsubstituted or substituted with one to three substituents selectedfrom R^(b); R¹ is selected from the group consisting of: (1) —SO₂NH₂,(2) —C(O)NH₂, and (3) —OH; R² is hydrogen; R³ is selected from the groupconsisting of: (1) piperidine, (2) azepane, and (3) morpholine, whereinR³ is unsubstituted or substituted with one to six substituents selectedfrom R^(c;) or a pharmaceutically acceptable salt thereof.
 11. Acompound selected from: 1)5-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinicacid; 2)4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)picolinicacid; 3)N-(6-cyanopyridin-3-yl)-2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamide;4)2-(azepan-1-yl)-N-(5-(methylsulfonyl)pyridin-3-yl)-5-(trifluoromethyl)nicotinamide;5)2-(3-(hydroxymethyl)piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;6)2-(azepan-1-yl)-N-(5-carbamoylpyridin-3-yl)-5-(trifluoromethyl)nicotinamide;7)2-(4,4-difluoro-1-piperidyl)-6-methyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;8)5-chloro-2-(4,4-difluoro-1-piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;9)6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(5-sulfamoylpyridin-3-yl)nicotinamide;10)5,6-dicyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;11)2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;12)5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;13)5-cyclobutyl-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;14)5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;15)2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;16)6-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;17)2-(4,4-difluoroazepan-1-yl)-5,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;18)5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide;19)5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;20)6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;21)5-chloro-6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;22)6-cyclobutyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;23)2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;24)2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;25)5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-nicotinamide;26)2-(5,5-Difluoro-2-oxoazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;27)2-(4,4-Dichloropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;28)5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;29)N-[2-(tert-butylsulfamoyl)pyridin-4-yl]-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methoxy-pyridine-3-carboxamide;30)5-cyano-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-nicotinamide;31)5-(cyclopropylethynyl)-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;32)5-(cyclopropylmethyl)-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;33)(S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;34)(R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)-nicotinamide;35)(R)-2-(4,4-dichloro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;36)(S)-2-(4,4-dichloro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;37)2-(4,4-Dichloroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;38)2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;39)5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-6-methyl-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;40)(S)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;41)(R)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;42)(S)-2-(3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;43)(R)-2-(3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;44)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[(1S,5S)-1-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl]pyridine-3-carboxamide;45)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[(1R,5R)-1-(trifluoromethyl)-3-azabicyclo[3.2.0]heptan-3-yl]pyridine-3-carboxamide;46)N-(2-sulfamoylpyridin-4-yl)-2-((1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl)-5-(trifluoromethyl)nicotinamide;47)2-[(1S,6S)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;48)2-[(1R,6R)-7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]heptan-3-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;49)2-((1R,5S)-8,8-difluoro-3-oxaoctan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;50)2-((1R,5S)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;51)2-((1S,5R)-6,6-difluoro-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;52)(R)-2-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;53)(S)-2-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;54)2-((1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;55)2-((1S,6S)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;56)2-((1R,6R)-7,7-difluoro-3-azabicyclo[4.1.0]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;57)2-[(1R,4R)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;58)2-[(1S,4S)-5,5-difluoro-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;59)(R)-2-(4,4-difluoro-2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;60)(S)-2-(4,4-difluoro-2-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;61)2-((3R,4s,5S)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;62)2-((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;63)2-[(3S,4S)-4-hydroxy-3-methyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;64)2-[(3S,4r,5R)-4-hydroxy-3,5-dimethyl-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;65)2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;66)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide;67)2-[3-(3,5-difluorophenyl)-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;68)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[4-(trifluoromethyl)-1-piperidyl]pyridine-3-carboxamide;69)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[[4-(trifluoromethyl)phenyl]methyl]-1-piperidyl]pyridine-3-carboxamide;70)N-(2-sulfamoyl-4-pyridyl)-2-thiomorpholino-5-(trifluoromethyl)pyridine-3-carboxamide;71)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyridine-3-carboxamide;72)2-(3-benzyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;73)2-[3,3-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;74)2-(2,2-dimethylmorpholin-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;75)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[8-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]pyridine-3-carboxamide;76)N-(2-sulfamoyl-4-pyridyl)-2-[4-(trifluoromethoxy)isoindolin-2-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;77)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[2-[4-(trifluoromethyl)phenyl]morpholin-4-yl]pyridine-3-carboxamide;78)N-(2-sulfamoyl-4-pyridyl)-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;79)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)azetidin-1-yl]pyridine-3-carboxamide;80)2-(3-pyrazol-1-ylpyrrolidin-1-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;81)2-[2-(4-fluorophenyl)-1-piperidyl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;82)2-(2,3,3a,5,6,6a-hexahydrofuro[3,2-b]pyrrol-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;83)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[3-[4-(trifluoromethyl)phenoxy]azetidin-1-yl]pyridine-3-carboxamide;84)N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-2-[4-[3-(trifluoromethyl)phenoxy]-1-piperidyl]pyridine-3-carboxamide;85)2-[4-(cyclopropylmethyl)-3-oxo-piperazin-1-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoro-methyl)pyridine-3-carboxamide;86)N-(2-sulfamoyl-4-pyridyl)-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;87)5-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;88)2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;89)2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;90)(S)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;91)(R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;92)2-[(2R)-6,6-dimethyl-2-(trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;93)2-(2,2-dimethyl-1,4-oxazepan-4-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;94)2-[(7S)-7-methyl-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;95)N-[2-(tert-butylsulfamoyl)-4-pyridyl]-5-chloro-2-(4,4-difluoroazepan-1-yl)pyridine-3-carboxamide;96)2-[(2S)-2-methylmorpholin-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;97)2-[(2R)-2-methyl-1,4-oxazepan-4-yl]-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;98)2-(3-hydroxy-3-methyl-1-piperidyl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;99)2-(6-fluoro-1,1-dimethyl-isoindolin-2-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)-pyridine-3-carboxamide;100)2-(4,4-difluoro-5-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;101)5-chloro-2-[(7R)-7-(difluoromethyl)-1,4-oxazepan-4-yl]-6-methyl-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;102)5-chloro-2-[(7S)-7-(difluoromethyl)-1,4-oxazepan-4-yl]-6-methyl-N-(2-sulfamoylpyridin-4-yl)pyridine-3-carboxamide;103)(R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;104)(S)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(7-(trifluoromethyl)-1,4-oxazepan-4-yl)nicotinamide;105)2-[(2S,7R)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl]-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;106)2-((2R,7S)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;107)2-((2R,7R)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;108)2-((2S,7S)-2-methyl-7-(trifluoromethyl)-1,4-oxazepan-4-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;109)(S)-5-chloro-2-(2-(difluoromethyl)morpholino)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;110)(R)-5-chloro-2-(2-(difluoromethyl)morpholino)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;111)N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide;112)(R)—N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)nicotinamide;113)N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-2-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridine-3-carboxamide;114)(S)-2-(3-cyanopyrrolidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;115)(R)-2-(3-cyanopyrrolidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;116)2-(4,4-difluoro-3-methylazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;117)2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;118)22-((2R,6S)-2-ethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;119)2-((2S,6R)-2-ethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;120)(R)-2-(2,2-dimethyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;121)(S)-2-(2,2-dimethyl-6-(trifluoromethyl)-morpholino)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;122)4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;123)6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)pyridine-3-carboxamide;124)2-(azepan-1-yl)-N-(2-sulfamoyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;125)2-(azepan-1-yl)-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;126)2-(azepan-1-yl)-N-(6-sulfamoyl-2-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;127)2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide;128)N-(2-methoxypyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)nicotinamide;129)2-(4,4-difluoroazepan-1-yl)-N-(5-sulfamoyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;130)2-(azepan-1-yl)-N-(5-sulfamoyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;131)2-(4,4-difluoroazepan-1-yl)-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;132)2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-(methylsulfonyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide;133)2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoro-methyl)-pyridine-3-carboxamide;134)2-[(3S)-4,4-difluoro-3-methyl-1-piperidyl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoro-methyl)-pyridine-3-carboxamide;135)N-(2-cyano-4-pyridyl)-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]-5-(trifluoro-methyl)-pyridine-3-carboxamide;136)N-(2-methylsulfonyl-4-pyridyl)-2-[(1R,5S)-6,6,7,7-tetrafluoro-3-azabicyclo[3.2.0]heptan-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;137)2-[(1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl]-N-(2-methylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;138)2-[(1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl]-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;139)(R)—N-(2-cyanopyridin-4-yl)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-5-(trifluoromethyl)-nicotinamide;140)(S)—N-(2-cyanopyridin-4-yl)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-5-(trifluoromethyl)-nicotinamide;141)4-(2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)-picolinamide;142)N-(2-carbamoyl-4-pyridyl)-2-[(3S)-4,4-difluoro-3-methyl-1-piperidyl]-5-(trifluoromethyl)-pyridine-3-carboxamide;143)N-(2-carbamoyl-4-pyridyl)-2-[(3R)-4,4-difluoro-3-methyl-1-piperidyl]-5-(trifluoromethyl)-pyridine-3-carboxamide;144)2-(4,4-difluoropiperidin-1-yl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)nicotinamide;145)5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;146)5-chloro-6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;147)(R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)nicotinamide;148)(S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)nicotinamide;149)(S)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;150)(R)-5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)nicotinamide;151)6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;152)6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;153)6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;154)5-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoyl-pyridin-4-yl)nicotinamide;155)6-chloro-2-(4,4-difluoropiperidin-1-yl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;156)2-(4,4-difluoroazepan-1-yl)-5-(difluoromethoxy)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;157)5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;158)2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;159)2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide; 160)4-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)nicotinamido)pyridine-2-sulfonicacid; 161)2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethoxy)nicotinamide162)2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;163)5-(tert-butyl)-2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;164)5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methyl)-nicotinamide;165)5-cyclopropyl-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoro-methoxy)-nicotinamide;166)2-(4,4-difluoropiperidin-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(2,2,2-trifluoro-ethoxy)-nicotinamide;167)2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;168)6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoro-methyl)nicotinamide;169)2-(azepan-1-yl)-N-(5-fluoropyridin-3-yl)-5-(trifluoromethyl)nicotinamide;170)2-(azepan-1-yl)-5-chloro-N-(2-methoxy-4-pyridyl)-4,6-dimethyl-pyridine-3-carboxamide;171)2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;172)5-chloro-2-(4,4-difluoro-1-piperidyl)-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;173)2-(6-azaspiro[2.5]octan-6-yl)-5-chloro-4,6-dimethyl-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;174)5-chloro-4,6-dimethyl-2-(1-piperidyl)-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;175)2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(5-sulfamoyl-3-pyridyl)pyridine-3-carboxamide;176)2-(azepan-1-yl)-N-(5-cyano-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;177)2-(azepan-1-yl)-N-(5-methoxy-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;178)2-(azepan-1-yl)-N-(5-methyl-3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;179)2-(azepan-1-yl)-N-[5-(hydroxymethyl)-3-pyridyl]-5-(trifluoromethyl)pyridine-3-carboxamide;180)2-(azepan-1-yl)-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;181)2-(azepan-1-yl)-N-(2-ethylsulfonyl-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide;182)2-(azepan-1-yl)-5-(trifluoromethyl)-N-[5-(trifluoromethyl)-3-pyridyl]pyridine-3-carboxamide;183)2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;184)5-chloro-4,6-dimethyl-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;185) 4-(2-(azepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;186)5-bromo-2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;187)2-(4,4-difluoropiperidin-1-yl)-5-phenyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;188)2-(4,4-difluoropiperidin-1-yl)-5-(piperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;189)2-(4,4-difluoropiperidin-1-yl)-5-(1H-pyrazol-1-yl)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;190)N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-5-(trifluoromethyl)-nicotinamide;191)5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide;192)2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;193)5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(piperidin-1-yl)nicotinamide;194)2-(azepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;and 195)2-(azepan-1-yl)-5-chloro-4,6-dimethyl-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 12. A compound selectedfrom: 1)5-chloro-2-(4,4-difluorocyclohexyl)-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;2)5-chloro-2-cycloheptyl-4,6-dimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide3)5-chloro-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrazine-2-carboxamide;4)5-chloro-4,6-dimethyl-2-(4-methylcyclohexyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;and 5)5-chloro-2-(4,4-difluoroazepan-1-yl)-N,4,6-trimethyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 14.A method of treating a disorder, condition or disease that is responsiveto the inhibition of Na_(v)1.8 channel activity in a patient in needthereof comprising administration of a therapeutically effective amountof a compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the disorder is selected from: pain disorder, acough disorder, an acute itch disorder or chronic itch disorder.
 15. Themethod of claim 14 wherein the disorder is a pain disorder.
 16. Themethod of claim 15 wherein the pain disorder is selected from: acutepain, inflammatory pain, or neuropathic pain.
 17. A compound selectedfrom: 1)(S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;2)(R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;3)2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;4)2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;5)5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;6)5-chloro-6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;7)5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;8)2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;9)2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;10)2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide; 11)5-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;12)4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;13)5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydro-pyridin-4-yl)nicotinamide;and 14)2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;or a pharmaceutically acceptable salt thereof.
 18. A compound which is(S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 19. A compound which is(R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 20. A compound which is5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;or a pharmaceutically acceptable salt thereof.
 21. A compound which is2-(4,4-difluoro-piperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.
 22. A compound which is5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide;or a pharmaceutically acceptable salt thereof.